WO2000056757A1 - Immunomodulatory steroids, in particular the hemihydrate of 16.alpha.-bromoepiandrosterone - Google Patents

Immunomodulatory steroids, in particular the hemihydrate of 16.alpha.-bromoepiandrosterone Download PDF

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Publication number
WO2000056757A1
WO2000056757A1 PCT/US2000/007883 US0007883W WO0056757A1 WO 2000056757 A1 WO2000056757 A1 WO 2000056757A1 US 0007883 W US0007883 W US 0007883W WO 0056757 A1 WO0056757 A1 WO 0056757A1
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WIPO (PCT)
Prior art keywords
infection
bromo
subject
androstene
hydroxy
Prior art date
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PCT/US2000/007883
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English (en)
French (fr)
Inventor
Clarence Nathaniel Ahlem
James Martin Frincke
Luis Daniel Dos Anjos De Carvalho
William Heggie
Patrick T. Prendergast
Christopher L. Reading
Krupakar Paul Thadikonda
Russell Neil Vernon
Original Assignee
Hollis-Eden Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority to RU2006133273/04A priority Critical patent/RU2417792C2/ru
Priority to HK02106613.2A priority patent/HK1046002B/zh
Priority to BR0009476-5A priority patent/BR0009476A/pt
Priority to APAP/P/2001/002285A priority patent/AP2001002285A0/en
Priority to NZ513803A priority patent/NZ513803A/en
Priority to JP2000606618A priority patent/JP2002540119A/ja
Priority to HU0203429A priority patent/HUP0203429A3/hu
Priority to AU39190/00A priority patent/AU781997B2/en
Priority to CA002365081A priority patent/CA2365081A1/en
Application filed by Hollis-Eden Pharmaceuticals, Inc. filed Critical Hollis-Eden Pharmaceuticals, Inc.
Priority to AT00918365T priority patent/ATE259825T1/de
Priority to EP00918365A priority patent/EP1163256B1/en
Priority to IL14491600A priority patent/IL144916A0/xx
Priority to DE60008353T priority patent/DE60008353T2/de
Publication of WO2000056757A1 publication Critical patent/WO2000056757A1/en
Priority to NO20014588A priority patent/NO320801B1/no
Priority to AU2005211675A priority patent/AU2005211675B2/en
Priority to NO20056167A priority patent/NO20056167L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to methods to make and use steroids, such as 16 ⁇ -bromo- 3 ⁇ -hydroxy-5 ⁇ -androstane-17-one (16 ⁇ -bromoep ⁇ androsterone or hereafter "BrEA") and new analogs thereof
  • BrEA 16 ⁇ -bromo- 3 ⁇ -hydroxy-5 ⁇ -androstane-17-one
  • the present invention also relates to methods to make the compounds, compositions and formulations.
  • compositions containing BrEA that were used to deliver the compound to cells or cell extracts usually included a significant amount of water
  • Such compositions contained solvents such as dioxane or dimethylsulfoxide (“DMSO”), which contained water, or an aqueous cyclodextnn solutions to facilitate compound delivery to cells, see, e g , J Pharmacol Exp Ther 1998, 285 876-83, Cancer Res 1986 46 3389-95, Carcinogenesis 1985 6 333-35, Carcinogenesis 1981 2 717-721 , Carcinogenesis 1981 2 683-86
  • Such compositions are typically delivered to animals by injection or to cells in tissue culture by addition to cell culture medium
  • European publication number EP 429 187 describes formulations that contain DHEA or BrEA and polyvinylpyrrohdone and crosslinked polyvinylpyrrohdone
  • helper T cells designated Th1 in the murine system facilitate immune effector functions that are typically dominated by cell-mediated responses
  • helper T cells designated Th2 cells facilitate immune effector functions that are typically dominated by humoral responses
  • a vigorous Th1 response is usually needed to clear infections or to slow the progression of an infection
  • the cytokines associated with the Th2 response tend to suppress the immune system's capacity to mount a vigorous Th1 response at the same time
  • the converse is also generally true
  • mammalian immune responses begin to result in an increasing Th2 response the Th1 response to the same condition tends to weaken Weak Th1 responses may be associated with progression of some infections or other conditions, see, e g , M Cle ⁇ ci and G M Shearer, Immunol Today 14 107-1 1 1 , 1993, M Clenci and G M Shearer, Immunol Today 14 107-1 1 1 , 1993, M Clenci and G M Shearer, Immunol Today 14 107-1 1 1 , 1993, M Clenci
  • compositions formulations or methods accomplish one or more of the following objects
  • One object of the invention is to provide new steroid compounds or analogs that are suitable for therapeutic and other applications such as immune modulators Invention objects further include providing BrEA hemihydrate (BrEA 2 ⁇ 2 0) compositions that comprise BrEA hemihydrate and methods to make and use it Another object of the invention is to provide liquid compositions and formulations that comprise a formula 1 compound(s), and that comprise about 3% (v/v) or less of water Another object is to provide compositions one can use as intermediates to prepare human pharmaceutical and veterinary formulations containing a formula 1 compound(s) Another object is to provide intermittent dosing methods to deliver a formula 1 compound to a subject to enhance Th1 immune responses Further objects are to provide methods to modulate innate immunity or to enhance Th1 immune responses in a subject by administering to the subject a formula 1 compound(s) such as BrEA Other objects are to provide methods to inhibit pathogen, e g , viral, replication in a subject by administering to the subject a formula 1 compound(s) such as BrE
  • Figure 1 is an FTIR (Fourier transform infrared) spectrum obtained by USP method
  • Figure 2 is a FTIR spectrum obtained by USP method ⁇ 197> of anhydrous BrEA that was prepared by precipitation of BrEA from anhydrous methanol
  • Figure 3 shows a DSC endotherm of BrEA hemihydrate that was prepared by precipitation of BrEA from ethanol and water
  • Figure 4 shows a DSC endotherm of anhydrous BrEA that was prepared by precipitation of BrEA from anhydrous methanol
  • Figure 5 is an XRD (powder
  • Figure 6 is a FTIR spectrum obtained by USP method ⁇ 197> of BrEA hemihydrate that was prepared by precipitation of BrEA from acetone and water
  • the invention provides BrEA hemihydrate
  • invention embodiments include a composition comprising a compound of formula 1
  • composition comprises less than about 3% v/v water and wherein,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 10 independently are -H, -OR PR , -SR PR , -N(R PR ) 2 , -O-Si- (R 3 ) 3 , -CN, -N0 2 , an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an ammo acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl
  • R 3 and both R 4 together comprise a structure of formula 2
  • R' is -CHRN -CHR 1U -CHR . 10 -CHR 10 -CHR 10 -CHR 10 CHR 10 -O-CHR 10 - -CHR 10 -S-CHR 10 -, -CHR 10 -NR PR -CHR 10 O-, -O-CHR 10 -, -S-, -S-CHR 10 NR - or -NR PR
  • CHR 10 R 8 and R 9 independently are -CHR 10 -, -CHR 10 -CHR 10 -, -0-, -O-CHR 10 -, -S-, -S- CHR 10 -, -NR PR - or -NR PR -CHR 10 -, or R 8 or R 9 independently is absent, leaving a 5- membered ring,
  • R 13 independently is C ⁇ . 6 alkyl
  • R 16 independently are -CH 2 -, -0-, -S- or -NH-,
  • D is a heterocycle or a 4-, 5-, 6- or 7-membered ring that comprises saturated carbon atoms, wherein 1 , 2 or 3 ring carbon atoms of the 4-, 5-, 6- or 7-membered ring are optionally independently substituted with -0-, -S- or -NR PR - or where 1 , 2 or 3 hydrogen atoms of the heterocycle or where 1 or 2 hydrogen atoms of the 4-, 5-, 6- or 7-membered ring are substituted with -OR PR , -SR PR , -N(R PR ) 2 , -0-S ⁇ -(R 13 ) 3 , -CN, -N0 2 , an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an ammo acid, a peptide
  • the invention provides a compound of formula 1 , wherein two or three of R 7 , R 8 and R 9 independently are not -CHR 10 -, wherein the compound is optionally present in a composition that comprises one or more excipients suitable for human pharmaceutical use or for veterinary use
  • Invention embodiments also include a compound of formula 1
  • R 1 R 2 , R 3 , R 4 , R 5 R 6 and R 0 independently are -H, -OR PR -SR PR -N(R PR ) 2 , -O-Si (R ) 3 , -CN, -N0 2 , an ester a thioester a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester a sulfite ester a sulfate ester an amide an am o acid, a peptide, an ether a thioether an acyl group a thioacyl group a carbonate a carbamate, a thioacetal, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted mono
  • R 3 and R 4 together comprise a structure of formula 2
  • R 7 is -CHR 10 -, -CHR 10 -CHR 10 -, -CHR 0 -CHR 10 -CHR 10 -, -CHR 10 -O-CHR 10 -,
  • R 8 and R 9 independently are -CHR 10 -, -CHR 10 -CHR 10 -, -0-, -O-CHR 10 -, -S-, -S- CHR 10 -, -NR PR - or -NR PR -CHR 10 -, or R 8 or R 9 independently is absent, leaving a 5- membered ring,
  • R 13 independently is d 6 alkyl
  • D is a heterocycle or a 4-, 5-, 6- or 7-membered ring that comprises saturated carbon atoms, wherein 1 , 2 or 3 ring carbon atoms of the 4-, 5-, 6- or 7-membered ring are optionally independently substituted with -O- -S- or -NR PR - or where 1 , 2 or 3 hydrogen atoms of the heterocycle or where 1 or 2 hydrogen atoms of the 4- 5-, 6- or 7-membered ring are substituted with -OR PR , -SR PR , -N(R PR ) 2 , -0-S ⁇ -(R 13 ) 3 , -CN, -N0 2 , an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an ammo acid, a peptide,
  • Embodiments include liquid formulations that comprise a formula 1 compound, one or more excipients and less than about 3% water, wherein the formulation is optionally disposed in containers that exclude water
  • Another embodiment is a method comprising intermittent administration of a formula 1 compound, to a subject having a pathological condition, such as a viral or parasite infection
  • a further embodiment is a method to modulate a subject's innate immunity, Th1 immune responses or Th2 immune responses comprising administering a formula 1 compound to a subject
  • invention formulation means an invention composition that one can administer parenterally to a human or animal without further manipulations that change the ingredients or the ingredient proportions that are present Formulations are suitable for human or veterinary applications
  • An "invention composition” is a composition that is an intermediate one can use to make the invention formulations, i e , a change(s) in an ⁇ ngred ⁇ ent(s) or its amount(s) is needed to make a formulation
  • invention compositions include compositions where further processing is required before it is a formulation, e g , mixing or addition of a desired amount of an ingredient
  • excipient means a component or an ingredient that is acceptable in the sense of being compatible with the other ingredients of invention compositions or formulations and not overly deleterious to the patient or animal to which the formulation is to be administered
  • excipients include liquids such as benzyl benzoate, cottonseed oil N,N-d ⁇ methylacetam ⁇ de, a C 2 12 alcohol (e g ,
  • a "subject” means a human or animal Usually the animal is a vertebrate such as a primate rodent, domestic animal or game animal Primates include chimpanzees, cynomologous monkeys, spider monkeys, and macaques, e g , Rhesus Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, felines, e g , domestic cat, canines, e.g., dog, avians, e g , chicken, emu, ostrich, and fish, e g , trout, catfish and salmon. Subject includes any subset of the foregoing, e g , all of the above, but excluding one or more groups or species such as humans, primates or rodents
  • Alkyl as used here means linked normal, secondary, tertiary or cyclic carbon atoms, i e , linear, branched or cyclic
  • the number of carbon atoms in an alkyl group or moiety is 1 to about 20, unless otherwise specified, e g , C, 8 alkyl means an alkyl moiety containing 1 , 2, 3, 4, 5, 6, 7 or 8 carbon atoms Examples include methyl, ethyl, 1-propyl (n-propyl), 2-propyl (/-propyl, -CH(CH 3 ) 2 ), 1 -butyl (n-butyl), 2-methyl-1-propyl (/-butyl, - CH 2 CH(CH 3 ) 2 ), 2-butyl (s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (f-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl), 2-p
  • the number of carbon atoms in an alkenyl group or moiety is 2 to about 20 unless otherwise specified, e g , C, 8 alkenyl means an alkenyl moiety containing 1 , 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • Alkynyl means linked normal, secondary, tertiary or cyclic carbon atoms where one or more triple bonds (-C ⁇ C-) are present typically 1 , 2 or 3 usually 1 The number of carbon atoms in an alkynyl group or moiety is 2 to about 20, unless otherwise specified, e g , Ci 8 alkynyl means an alkynyl moiety containing 1 , 2, 3 4, 5, 6 7 or 8 carbon atoms
  • Aryl means phenyl or naphthyl
  • Substituted alkyl "substituted alkenyl” and “substituted alkynyl” mean an alkyl, alkenyl or alkynyl group that has a subst ⁇ tuent(s) linked to a carbon atom or subst ⁇ tuent(s) that interrupt a carbon atom chain
  • Substituents include ethers (-0-), ketones (-C(O)-), -
  • Heterocycle or “heterocyclic” includes by way of example and not limitation the heterocycles described in Paquette, Leo A , "Principles of Modern
  • heterocycles include by way of example and not limitation py ⁇ dyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, py ⁇ midinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, mdolyl, indolenyl, quinolmyl, isoquinolinyl, benzimidazolyl, pipe ⁇ dinyl, 4-p ⁇ pe ⁇ donyl,
  • nitrogen bonded heterocycles are bonded at position 1 of an azi ⁇ dine, azetidme, pyrrole, pyrrolidme, 2-pyrrol ⁇ ne, 3-pyrrol ⁇ ne, imidazole, imidazolidine, 2- ⁇ m ⁇ dazol ⁇ ne, 3- ⁇ m ⁇ dazol ⁇ ne, pyrazole, pyrazolme, 2-pyrazol ⁇ ne, 3- pyrazolme, pipe ⁇ dine, piperazme, indole, indolme 1 H- ⁇ ndazole, position 2 of a isomdole, or isomdoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carbo ne
  • nitrogen bonded heterocycles include 1-az ⁇ dyl, 1-azetedyl, 1-pyrrolyl, 1- imidazoiyl, 1-pyrazolyl, and 1-p ⁇ pe ⁇ d ⁇ nyl
  • Heteroaryl means an aromatic ring or two or more fused rings that contain one or more aromatic rings where the ring or fused rings comprise 1 , 2, 3 or more heteroatoms, usually oxygen (-0-), nitrogen (-NX-) or sulfur (-S-) where X is -H, a protecting group or C,. 6 alkyl, usually -H Examples are as described for heterocycle
  • Alcohol as used herein, usually in the context of excipients, means an alcohol that comprises a C 2 12 alkyl moiety substituted at a hydrogen atom with one hydroxyl group Alcohols include ethanol, n-propanol /-propanol, n-butanol, /-butanol, s-butanol, t- butanol, n-pentanol, /-pentanol, n-hexanol, cyclohexanol, n-heptanol, n-octanol, n-nonanol and n-decanol
  • the carbon atoms in alcohols can be straight, branched or cyclic Alcohol includes any subset of the foregoing, e g , C 2 4 alcohols (alcohols having 2, 3 or 4 carbon atoms)
  • Halogen means fluorine, chlorine, bromine or iodine
  • Protecting group means a moiety that prevents the atom to which it is linked from participating in unwanted reactions
  • R PR may be hydrogen or a protecting group for the oxygen atom found in a hydroxyl
  • R PR may be hydrogen or a carboxyl protecting group
  • R PR may be hydrogen or a protecting group for sulfur in thiols for instance and for -NHR PR or -N(R PR ) 2 -
  • R PR may be hydrogen or a nitrogen atom protecting group for primary or secondary amines Hydroxyl, amme and other reactive groups are found in formula 1 compounds at, e g , R or R 2
  • These groups may require protection against reactions taking place elsewhere in the molecule
  • the protecting groups for oxygen, sulfur or nitrogen atoms are usually used to prevent unwanted reactions with electrophilic compounds, such as acylating used, e g., in steroid
  • esters means a moiety that comprises a -C(0)-0- structure
  • esters as used here comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2-20 carbon atoms) and 0 to about 10 independently selected heteroatoms (e g , O, S, N, P, Si), where the organic moiety is bonded to a formula 1 steroid nucleus at, e g , R 1 or R 2 through the -C(0)-0- structure, e g , organic mo ⁇ ety-C(0)-0- steroid or organic mo ⁇ ety-0-C(0)-stero ⁇ d
  • the organic moiety usually comprises one or more of any of the organic groups described above, e g , Ci 20 alkyl moieties, C 2 20 alkenyl moieties, C 2 20 alkynyl moieties, aryl moieties, C 2 9 heterocycles or substituted derivatives of any of these, e g , comprising 1 , 2, 3 4 or
  • Thioester' means a moiety that comprises a -C(S)-0- structure
  • thioesters as used here comprise an organic moiety containing about 1 -50 carbon atoms (e g , about 2-20 carbon atoms) and 0 to about 10 heteroatoms (e g , O, S, N, P, Si), where the organic moiety is bonded to a formula 1 steroid nucleus at R 2 through the -C(S)- O- structure, e g , organic mo ⁇ ety-C(S)-0-stero ⁇ d or organic mo ⁇ ety-0-C(S)-stero ⁇ d
  • the organic moiety is as described above for esters
  • Thioacetal means a moiety that comprises a -C(0)-S- structure
  • thioacetals as used here comprise an organic moiety containing about 1 -50 carbon atoms (e g , about 2-20 carbon atoms) and 0 to about 10 heteroatoms (e g g
  • Phosphoester or "phosphate ester” means a moiety that comprises a -0-P(OR PR )(0)-0- structure where R PR is hydrogen (-H), a protecting group or an organic moiety as described for esters
  • phosphoesters as used here comprise a hydrogen atom, a protecting group or an organic moiety containing about 1-50 carbon atoms and 0 to about 10 heteroatoms (e g , O, S, N, P, Si) linked to a formula 1 steroid nucleus at R 1 -R 6 , R 10 , R 15 , R 17 or R 18 through the -0-P(0)(0)-0- structure, e g , organic mo ⁇ ety-0-P(0)(OH)-0-stero ⁇ d
  • the organic moiety is as described above for esters
  • Phosphothioester means a moiety that comprises a -0-P(SR pp )(0)-0- structure where R PR is -H, a protecting group or an organic moiety as described for esters
  • phosphothioesters as used here comprise a hydrogen atom, a protecting group or an organic moiety containing about 1 -50 carbon atoms and 0 to about 10 heteroatoms (e g , O, S, N, P, Si) linked to a formula 1 steroid nucleus at R 1 -R 6 , R 0 , R 15 , R 7 or R 18 through the -0-P(0)(0)-0- structure, e g , organic mo ⁇ ety-0-P(0)(SH)-0-stero ⁇ d.
  • the organic moiety is as described above for esters
  • Phosphonoester means a moiety that comprises a -P(OR PR )(0)-0- structure where R PR is -H, a protecting group or an organic moiety as described for esters
  • phosphonoesters as used here comprise a hydrogen atom, a protecting group or an organic moiety containing about 1-50 carbon atoms and 0 to about 10 heteroatoms (e g , O, S, N, P, Si) linked to a formula 1 steroid nucleus at R 1 -R 6 , R 0 , R 15 , R 17 or R 18 through the -P(OR PR )(0)-0- structure, i e , organic mo ⁇ ety-P(OR PR )(0)-0-stero ⁇ d or steroid- P(OR PR )(0)-0-organ ⁇ c moiety
  • the organic moiety is as described above for esters
  • Phosphiniester means a moiety that comprises a -P(OR PR )-0- structure where
  • R PR is -H, a protecting group or an organic moiety as described for esters
  • phosphiniesters as used here comprise a hydrogen atom, a protecting group or an organic moiety containing about 1-50 carbon atoms and 0 to about 10 heteroatoms (e g , O, S, N, P, Si) linked to a formula 1 steroid nucleus at R 1 -R 6 , R 10 , R 15 , R 17 or R 18 through the - P(OR PR )-0- structure, i e , organic mo ⁇ ety-P(OR PR )-0-stero ⁇ d or stero ⁇ d-P(OR PR )-0-organ ⁇ c moiety
  • the organic moiety is as described above for esters
  • “Sulfate ester' means a moiety that comprises a -0-S(0)(0)-0- structure
  • sulfate esters as used here comprise a hydrogen atom, a protecting group or an organic moiety containing about 1-50 carbon atoms and 0 to about 10 heteroatoms (e g , O S, N P, Si) linked to a formula 1 steroid nucleus at R 1 -R 6 , R 10 , R 15 R ⁇ or R 18 through the -0-S(0)(0)-0- structure, e g , organic mo ⁇ ety-0-S(0)(0)-0-stero ⁇ d
  • the organic moiety is as described above for esters
  • “Sulfite ester” means a moiety that comprises a -0-S(0)-0- structure
  • sulfite esters as used here comprise an organic moiety containing about 1-50 carbon atoms and 0 to about 10 heteroatoms (e g , O, S, N, P, Si) linked to a formula 1 steroid
  • Thioacetal means a moiety that comprises a -S-C(O)- structure
  • thioacetal groups as used here comprise an organic moiety containing about 1-50 carbon atoms and 0 to about 10 heteroatoms (e g , O, S, N, P, Si) linked to a formula 1 steroid nucleus at R 1 -R 6 , R 10 , R 5 , R 17 or R 18 through the -S-C(O)- structure, e g , organic moiety- S-C(0)-stero ⁇ d or stero ⁇ d-S-C(0)-organ ⁇ c moiety
  • the organic moiety is as described above for esters
  • Amide means an organic moiety as described for ester that comprises 1 , 2, 3, 4 or more -C(0)-NR PR - moieties, usually 1 or 2, where R PR is -H or a protecting group, R PR is usually H
  • the -C(0)NR PR - group is linked to the steroid nucleus at R 1 -R 6 , R 10 , R 15 , R 17 or R 18 , i e , organic mo ⁇ ety-C(0)NR PR -stero ⁇ d or stero ⁇ d-C(0)NR PR - organic moiety
  • “Ether” means an organic moiety as described for ester that comprises 1 , 2, 3, 4 or more -O- moieties, usually 1 or 2 In some embodiments, the -O- group is linked to the steroid nucleus at R 1 -R 6 , R 10 , R 15 , R 17 or R 18 , e g , organic mo ⁇ ety-0-stero ⁇ d "Thioether” means an organic moiety as described for ester that comprises 1 , 2, 3,
  • the -S- group is linked to the steroid nucleus at R 1 -R 6 R 0 , R 5 , R 7 or R 18 , e g , organic moiety-S-steroid
  • Acyl group means an organic moiety as described for ester that comprises 1 , 2, 3, 4 or more -C(O)- groups in some embodiments the -C(O)- group is linked to the steroid nucleus at R 1 -R 6 , R 10 , R 15 , R 7 or R 18 e g , organic mo ⁇ ety-C(0)-stero ⁇ d
  • Thioacyl means an organic moiety as described for ester that comprises 1 , 2, 3, 4 or more -C(S)- groups
  • the -C(S)- group is linked to the steroid nucleus at R 1 -R 6 , R 10 , R 15 , R 17 or R 8 , e g , organic mo ⁇ ety-C(S)-stero ⁇ d
  • Carbonate means an organic moiety as described for ester that comprises 1 , 2, 3, 4 or more -0-C(0)-0- structures
  • carbonate groups as used here comprise an organic moiety containing about 1 -50 carbon atoms and O to about 10 heteroatoms (e g , O, S, N, P, Si) linked to a formula 1 steroid nucleus at R 1 -R 6 R 10 R 15 R 17 or R 18 through the -0-C(0)-0- structure e g , organic mo ⁇ ety-0-C(0)-0-stero ⁇ d
  • “Carbamate” means an organic moiety as described for ester that comprises 1 , 2, 3 4 or more -0-C(0)NR PR - structures where R PR is -H, a protecting group or an organic moiety as described for ester
  • carbamate groups as used here comprise an organic moiety containing about 1 -50 carbon atoms and 0 to about 10 heteroatoms (e g , O, S, N, P, Si) linked to a formula 1 steroid nucleus at R 1 -R 6 , R 10 , R 15 , R 17 or R 18 through the -0-C(0)-NR PR - structure, e g , organic mo ⁇ ety-0-C(0)-NR PR -stero ⁇ d or stero ⁇ d-O-C(O)- NR PR -organ ⁇ c moiety
  • monosaccha ⁇ de means a polyhydroxy aldehyde or ketone having the empirical formula (CH2 ⁇ ) n where n is 3, 4, 5, 6 or 7
  • Monosaccha ⁇ de includes open chain and closed chain forms, but will usually be closed chain forms
  • Monosaccha ⁇ de includes hexofuranose and pentofuranose sugars such as 2'- deoxy ⁇ bose, ⁇ bose, arabmose, xylose, their 2'-deoxy and 3'-deoxy derivatives and their 2',3'-d ⁇ deoxy derivatives
  • Monosaccha ⁇ de also includes the 2', 3' dideoxydidehydro derivative of ⁇ bose
  • Monosaccha ⁇ des include the D-, L- and DL-isomers of glucose, fructose, mannose, idose, galactose, allose, gulose, altrose, talose, fucose, erythrose, threose, lyxo
  • Nucleoside includes 3TC, AZT, D4T, ddl, ddC, G, A, U, C, T, dG, dA, dT and dC.
  • Polymer includes biocompatible organic polymers, e g , PEGs and polyhydroxyalkyl polymers
  • PEG means an ethylene glycol polymer that contains about 20 to about 2000000 linked monomers, typically about 50-1000 linked monomers, usually about 100-300
  • Polyethylene glycols include PEGs containing various numbers of linked monomers, e g., PEG20, PEG30, PEG40, PEG60, PEG80, PEG100, PEG1 15, PEG 200, PEG 300, PEG400, PEG500, PEG600, PEG 1000, PEG1500, PEG2000, PEG 3350, PEG4000, PEG4600, PEG5000, PEG6000, PEG8000, PEG1 1000, PEG12000, PEG2000000 and any mixtures thereof
  • Am o acid means an ammo acid moiety that comprises any naturally-occurring or synthetic ammo acid residue, i e , any moiety comprising at least one carboxyl and at least one ammo residue directly linked by one, two three or more carbon atoms, typically one ( ⁇ ) carbon atom
  • the nature and identity of the intervening structure located between the carboxyl and ammo groups can have a variety of structures including those described herein
  • ammo acids linked to the steroid through the amine group have sufficient conformation and length to be capable of autocatalytic hydrolysis of the ammo acid-steroid bond and release of the steroid This can occur when the free carboxyl is generated in vivo by deeste ⁇ fication, deamidation or peptidolytic cleavage of the precursor containing a linkage between the ammo acid's amine group and the steroid Hydrolysis of the bond between an ammo acid's carboxyl or ammo group and the steroid can also occur by chemical
  • ammo acids corresponding to the residues employed in the invention compounds are naturally occurring and have no significant pharmacological activity per se
  • optimal pharmacokinetic activity may be achieved by using non-naturally occurring am o acid residues
  • the intervening structure may be as simple as methylene when the ammo acid residue is glycyl, or substituted methylene for other ⁇ am o acids
  • the structure ordinarily contains up to about 5 carbon or heteroatoms in the direct linkage between the ammo acid's carboxyl carbon and the amine nitrogen
  • ammo acids can comprise intervening ethylene propylene butylene or pentylene groups or their substituted analogs, such as for example, oxyesters or ethers in which oxygen replaces carbon and, as appropriate, hydrogen
  • An example of such an intervening structure would be -CH-0-C(R 22 )(R 23 )-, where R 22 and R 23 are independently selected hydrogen or organic moie
  • R 22 is -H, methyl or hydroxymethyl, usually -H
  • R 23 is a side chain or group of a naturally occurring ammo acid
  • Ammo acid side chains include analogs where the side chain is a Ci 15 homolog of the corresponding natural compound, e g , methylene, ethylene, propylene, butylene or a substituted derivative thereof, e.g , an alkyl, ether or alkoxy (e g , methoxy, ethoxy, propoxy) substituted derivative
  • carboxyl-containmg side chains if the C atom of the side chain carboxyl is linked by 5 or less atoms to the ⁇ then the carboxyl optionally will be blocked, e g by este ⁇ fication or amidation wherein the ester or amide bonds are hydrolyzable in vivo R 22 also is taken together with R 30 to form a proline residue (-CH2-)3
  • R 23 is generally a side group such as -
  • the ammo acid residue has the structure shown in the formulas below Ordinarily, n is 1 or 2, R 22 is -H and R 23 is a moiety containing one or more of the following groups ammo, carboxyl, amide, carboxyl ester, hydroxyl, C6-C aryl, ether (-0-), thioether (-S-), n- s- or t-alkyl (C
  • the R 22 and R 23 substituents can have a wide variety of structures including those disclosed herein, e g , esters, ethers or carbonates
  • any of the D, L, meso, threo or erythro (as appropriate) racemates or mixtures thereof fall within the scope of this invention
  • D isomers should be used
  • L isomers may be more versatile since they can be susceptible to both non-enzymatic as well as potential targeted enzymatic hydrolysis, and are more efficiently transported by amino acid or dipeptidyl transport systems in the gastrointestinal tract
  • am o acid residues include the following. Glycyl, aminopolycarboxyhc acids, e g , aspartic acid, ⁇ -hydroxyaspartic acid, glutamic acid, ⁇ - hydroxyglutamic acid, ⁇ -methylaspartic acid, ⁇ -methylglutamic acid, ⁇ , ⁇ -d ⁇ methylaspart ⁇ c acid, ⁇ -hydroxyglutamic acid, ⁇ , ⁇ -d ⁇ hydroxyglutam ⁇ c acid, ⁇ -phenylglutamic acid, ⁇ - methyleneglutamic acid, 3-am ⁇ noad ⁇ p ⁇ c acid, 2-am ⁇ nop ⁇ mel ⁇ c acid, 2-am ⁇ nosuber ⁇ c acid and 2-am ⁇ nosebac ⁇ c acid residues, ammo acid amides such as glutaminyl and asparagmyl, polyammo- or polybasic-monocarboxylic acids such as arginme, lysine, ⁇ - aminoalanine, ⁇ -aminobut
  • ammo acids are suitably employed in this invention.
  • ammo acids are capable of autocatalytically hydrolyzmg the ammo acid-steroid bond
  • they typically contain, or upon being hydrolyzed in vivo, contain a free carboxyl group or amine group
  • hydrophobic ammo acids such as mono-or di-alkyl or aryl am o acids, cycloalkylamino acids and the like
  • residues, together with R 29 - R 34 can contribute to cell permeability by modulating the lipophilicity of a formula 1 or formula 2 compound
  • the residue does not contain a sulfhydryl or guanidino substituent
  • R 1 -R 4 can comprise a 'peptide", i e , two or more am o acids as defined above Typically the ammo acids are linked through normal peptide bonds, i e , -CO-NH- between adjacent am o acid residues
  • Peptides comprise dipeptides (dimers), t ⁇ peptides (t ⁇ mers), short peptides of 4, 5, 6, 8, 10 or 15 residues, and longer peptides or proteins having about 100 or more residues
  • Invention compounds that comprise a peptide can be used as immunogens, prodrugs or as synthetic precursors for other steroid derivatives
  • the peptide will contain a peptidolytic enzyme cleavage site at the peptide bond linking the first residue and the next residue distal to the steroid residue Such cleavage sites are optionally flanked by enzymatic recognition structures, e g particular residues recognized by a hydrolytic enzyme, e g , a peptidas
  • Carboxypeptidases digest polypeptides by removing C-termmal residues, and are specific in many instances for particular C-termmal sequences
  • Such enzymes and their substrate requirements in general are well known
  • a dipeptide having a given pair of residues and a free carboxyl terminus is covalently bonded through its ⁇ -amino group to the steroid nucleus It is expected that the peptide will be cleaved by the appropriate dipeptidase, protease or by chemical hydrolysis, leaving the carboxyl of the proximal ammo acid residue to autocatalytically cleave the amidate bond
  • AA AR, AN, AD, AC, AE, AQ, AG, AH, Al, AL, AK AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, Rl, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, Dl, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, Cl, CL, CK, CM CF
  • Such dipeptides include species where both ammo acids are in the L configuration, the D configuration or mixtures of configurations T ⁇ peptides, i.e , 3 linked ammo acid residues, are also useful embodiments.
  • T ⁇ peptides include those where A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W or Y is linked by a standard peptide bond to the ammo or the carboxyl terminus of any of the dipeptides listed above
  • the sequence -X1-pro-X2- (where X1 is any ammo acid and X2 is hydrogen, any ammo acid residue or a carboxyl ester of proline) will be cleaved by luminai carboxypeptidase to yield X1 with a free carboxyl, which in turn autocatalytically cleaves the amidate bond X2 usually will be a benzyl ester of the carboxy group of X2
  • Other embodiments include tetrapeptides such as ones where any two of the dipeptides listed above, which may be the same or different dipeptides (e g , AA and AA linked together or, e g
  • the formula 1 or formula 2 compound comprises one or more ammo acids or peptides having the structure (A), (B) or (C) (A) R 32 -NH- ⁇ [C(R 29 )(R 30 )] b -C(O)-N(R 31 ) ⁇ r [C(R 29 )(R 30 )] a -C(O)-O-stero ⁇ d, (B) R 33 -0- ⁇ C(0)-[C(R 9 )(R 30 )] d -N(R 31 ) ⁇ g -C(0)-[C(R 29 )(R 30 )] c -N(R 31 )-0-steroid, or
  • (C) R 33 -O- ⁇ C(O)-[C(R 29 )(R 30 )] d -N(R 31 ) ⁇ -C(O)-[C(R 29 )(R 30 )] c -N(R 31 )-C(O)-O-stero ⁇ d, wherein (A), (B) or (C) are independently selected and they are bonded to 1 , 2, 3 or more of R 1 through R 4 , where each R 29 -R 31 is independently selected, R 29 independently are -H or a C1 -20 organic moiety (e g , d 6 alkyl, e g -CH 3 or -C 2 H 5 ), R 30 independently are the side chain of an amino acid, including the side chain of naturally occurring ammo acids as described above, e g , -H, -CH 3 , -CH 2 C 6 H 5 , R 31 is -H or a protecting group, R 32 and R 33 independently comprise -H,
  • R 29 is usually -H and R 30 may comprise - [C(R 34 ) ] n 2N(R PR )- where n2 is ON , 2, 3, 4, 5 or 6, R PR is -H or a protecting group and each R 34 independently is -H, C1-C20 optionally substituted alkyl, C6-C20 optionally substituted aryl, C -C2o optionally substituted alkylaryl, C -C2o optionally substituted arylalkyl, C1-C20 optionally substituted alkoxy, C6-C20 optionally substituted aryloxy or hydroxyl
  • Such compounds will contain a plurality of steroid moieties For example when both the epsilon ( ⁇ ) or delta ( ⁇ ) and alpha ( ⁇ ) am
  • compositions including pharmaceutically acceptable or salts that are relatively non-toxic
  • Some of the invention compounds have one or more moieties that carry at least a partial positive or negative charge in aqueous solutions, typically at a pH of about 4-10, that can participate in forming a salt, a complex, a composition with partial salt and partial complex properties or other noncovalent interactions, all of which we refer to as a "salt(s)" Salts are usually biologically compatible or pharmaceutically acceptable or non-toxic, particularly for mammalian cells Salts that are biologically toxic are optionally used with synthetic intermediates of invention compounds When a water-soluble composition is desired, monovalent salts are usually used Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention Examples of metal salts that are optionally prepared in this way are salts containing L ⁇ + , ⁇ a + , and K + A less soluble metal salt can be precipitated from the solution of a more soluble salt by adding a suitable metal compound Invention salts may be formed from acid addition
  • Salt(s) of invention compounds may comprise a combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary ammonium ions with the acid anion moiety of the phosphoric acid or phosphonic acid group, which may be present in invention polymers or monomers
  • Salts are produced by standard methods including dissolving free base in an aqueous aqueous-alcohol or aqueous-organic solution containing the selected acid, optionally followed by evaporating the solution
  • the free base is reacted in an organic solution containing the acid, in which case the salt usually separates directly or one can concentrate the solution
  • Suitable amine salts include amines having sufficient basicity to form a stable salt, usually amines of low toxicity including t ⁇ alkyl amines (t ⁇ propylamine, t ⁇ ethylamine, t ⁇ methylamine), procaine, dibenzylamine, N-benzyl-betaphenethylamine, ephenamine, N,N'-d ⁇ benzylethylened ⁇ am ⁇ ne, N-ethylpipe ⁇ dine, benzylamine and dicyclohexylamine.
  • amines of low toxicity including t ⁇ alkyl amines (t ⁇ propylamine, t ⁇ ethylamine, t ⁇ methylamine), procaine, dibenzylamine, N-benzyl-betaphenethylamine, ephenamine, N,N'-d ⁇ benzylethylened ⁇ am ⁇ ne, N-ethylpipe ⁇ dine, benzylamine and dicyclohexylamine.
  • Salts include organic sulfonic acid or organic carboxy c acid salts, made for example by addition of the acids to basic centers, typically amines
  • Exemplary sulfonic acids include C6-16 aryl sulfonic acids, C ⁇ -16 heteroaryl sulfonic acids and Ci-16 alkyl sulfonic acids such as phenyl sulfonic acid, a-naphthalene sulfonic acid, ⁇ -naphthalene sulfonic acid, (S)-camphorsulfon ⁇ c acid, methyl (CH3SO3H), ethyl (C2H5SO3H), n-propyl, /-propyl, n-butyl, s-butyl, /-butyl, t-butyl, pentyl and hexyl sulfonic acids
  • Exemplary organic carboxylic acids include Ci -16 alkyl, C6-16 aryl carboxylic acids and C4-I
  • Invention salts include those made from inorganic acids, e g , HF, HCl, HBr, HI, H2SO-4, H3PO4, Na2C ⁇ 3, K2CO3, CaC ⁇ 3, MgC03 and NaCI03
  • Suitable anions which are optionally present with a cation such a Ca , Mg , Li , Na or K , include arsenate, arsenite formate, sorbate, chlorate, perchlorate, pe ⁇ odate, dichromate, glycodeoxycholate, cholate, deoxycholate, desoxycholate, taurocholate, taurodeoxycholate, taurolithochoiate, tetraborate, nitrate, nitrite, sulfite, sulfamate, hyposulfite, bisulfite, metabisulfite, thiosulfate, thiocyanate, silicate, metasilicate, CN " , gluconate, gulcur
  • Salts also include the invention compound salts with one or more ammo acids
  • ammo acids are suitable, especially the naturally-occurring ammo acids found as protein components, although the ammo acid typically is one bearing a side chain with a basic or acidic group, e g , lysine, arginme histidine or glutamic acid, or a neutral group such as glycine, serine, threonine alanme isoleucme, or leucme
  • compositions include compounds in their un-ionized, as well as zwitte ⁇ onic form, and combinations with stoiochimet ⁇ c amounts of water as in hydrates Stereoisomers
  • the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions Both racemic and diasteromenc mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiome ⁇ c or diastereome ⁇ c partners, and these are all within the scope of the invention. Chiral centers may be found in invention compounds at, for example, R 1 , R2, R 3 and R 4 .
  • One or more of the following methods are used to prepare the enantiome ⁇ cally enriched or pure isomers herein
  • the methods are listed in approximately their order of preference, i e , one ordinarily should employ stereospecific synthesis from chiral precursors before chromatographic resolution before spontaneous crystallization
  • stereospecific synthesis is described in the examples Methods of this type conveniently are used when the appropriate chiral starting material is available and reaction steps are chosen do not result in undesired racemization at chiral sites
  • One advantage of stereospecific synthesis is that it does not produce undesired enantiomers that must be removed from the final product, thereby lowering overall synthetic yield in general, those skilled in the art would understand what starting materials and reaction conditions should be used to obtain the desired enantiomerically enriched or pure isomers by stereospecific synthesis If a suitable stereospecific synthesis cannot be empirically designed or determined with routine experimentation then those skilled in the art would turn to other methods
  • One method of general utility is chromatographic resolution of enantiomers on chiral chromatography resins These resins are packed in columns, commonly called Pirkle columns, and are commercially available The columns contain a chiral stationary phase The racemate is placed in solution and loaded onto the column, and thereafter separated by HPLC See for example, Proceedings Chromatographic Society - International Symposium on Chiral Separations, Sept
  • Another method entails converting the enantiomers in the mixture to diaste ⁇ omers with chiral auxiliaries and then separating the conjugates by ordinary column chromatography This is a very suitable method particularly when the embodiment contains free carboxyl, am o or hydroxyl that will form a salt or covalent bond to a chiral auxiliary Chirally pure ammo acids organic acids or organosulfonic acids are all worthwhile exploring as chiral auxiliaries, all of which are well known in the art.
  • Salts with such auxiliaries can be formed, or they can be covalently (but reversibly) bonded to the functional group
  • auxiliaries can be formed, or they can be covalently (but reversibly) bonded to the functional group
  • pure D or L ammo acids can be used to amidate the carboxyl group of invention embodiments that comprise a carboxyl group and then separated by chromatography
  • Enzymatic resolution is another method of potential value In such methods one prepares covalent derivatives of the enantiomers in the racemic mixture, generally lower alkyl esters (for example of carboxyl), and then exposes the derivative to enzymatic cleavage, generally hydrolysis
  • an enzyme must be chosen that is capable of stereospecific cleavage, so it is frequently necessary to routinely screen several enzymes If esters are to be cleaved, then one selects a group of esterases. phosphatases, and lipases and determines their activity on the derivative.
  • Typical esterases are from liver, pancreas or other animal organs, and include porcine liver esterase If the enatiome ⁇ c mixture separates from solution or a melt as a conglomerate, i.e., a mixture of enantiome ⁇ cally pure crystals, then the crystals can be mechanically separated, thereby producing the enantiomencally enriched preparation This method, however, is not practical for large-scale preparations and is of limited value for true racemic compounds Asymmetric synthesis is another technique for achieving enantiome ⁇ c enrichment.
  • a chiral protecting group is reacted with the group to be protected and the reaction mixture allowed to equilibrate If the reaction is enantiomencally specific then the product will be enriched in that enantiomer
  • expressions of a percentage of a liquid ingredient, e g , an excipient, in an invention composition or formulation mean the ingredient's percent by volume (v/v)
  • 20% propylene glycol means 20% v/v propylene glycol is present in an invention composition or formulation
  • the amount of excipient indicated in invention compositions is not affected by the form used, e.g., NF or USP grade solvent or excipient
  • an invention composition that comprises about 30% polyethylene glycol 300 NF can instead comprise a USP counterpart, provided that other limitations, such as the amount of water present, are not exceeded
  • innate immunity refers to one or more components typically associated with nonspecific immune defense mechanisms in a subject These components include the alternate complement pathway, e g , Factor B, Factor D and properdm, NK cells, phagocytes (monocytes, macrophages), neutrophils, eosinophils, dendritic cells, fibrocytes, anti-microbial chemicals, e g , defensms, physical barriers - skin, mucosal epithelium, and certain interleukms, chemokmes and cytokines
  • Innate immunity plays a role in resistance to intracellular parasite infections, e g , white blood cell infection, a liver infection, and other infections, e g , lymph node infections
  • Enhancement of innate immunity mechanism by formula 1 compounds or method described herein may enhance phagolysosome fusion or movement, which some pathogens, e g , intracellular bacteria such as mycobacte ⁇ a, or Listena inhibit
  • references to CD molecules, specific immune cell subsets, immune responses and the like generally use nomenclature that applies to molecules, cells or the like that are found in humans Analogs or counterparts of such molecules, cells or the like in other species may have a differing nomenclature, but are included in this invention
  • a description of the nomenclature and function of various CD molecules and immune cell subsets are as found in the scientific literature References to ThO, Th1 or Th2 cells and references to Th1 or Th2 immune responses in the context of human patients refers to the human counterparts of the murine ThO, Th1 or Th2 immune cells or responses
  • ThO Th1 or Th2 cells
  • Th1 or Th2 immune responses refers to the human counterparts of the murine ThO, Th1 or Th2 immune cells or responses
  • Immunosuppressive molecule means molecules such as cyclospo ⁇ n, cyclohexamide, mitomycm C, ad ⁇ amycin, taxol and amphote ⁇ cin B These molecules tend to have toxicities toward the immune system and are directly or indirectly immunosuppressive, i e , toxic to dividing cells or they can downregulate immunity
  • Step receptor means a gene product, typically a protein monomer or dimer that can bind to a hgand, e g , a natural steroid or an analog thereof, such as formula 1 compounds
  • Steroid receptors include orphan steroid receptors
  • Orphan steroid receptors are proteins for which the natural gand or
  • Powder X-ray diffraction (XRD) methods have been used to characterize various crystalline compounds (see, e g , U S Pharmacopoeia, volume 23, 1995, ⁇ 941 >, p 1843- 1845, U S Pharmacopeial Convention, Inc , Rockville, MD, Stout et al , X-Ray Structure Determination, A Practical Guide, MacMillan Co , New York, N Y , 1986)
  • the diffraction pattern, or portions thereof, obtained from a crystalline compound is usually diagnostic for a given crystal form, although weak or very weak diffraction peaks may not always appear in replicate diffraction patterns obtained from successive batches of crystals
  • the relative intensities of XRD bands, particularly at low angle X-ray incidence values (low Theta) may vary due to preferred orientation effects arising from differences in, e g , crystal habit, particle size or other measurement conditions Peaks on XRD spectra are typically defined at a given Theta value +/- about
  • a crystalline material such as BrEA hemihydrate
  • Other techniques that are used to identify or describe a crystalline material include melting point (MP), differential scanning calo ⁇ metry (DSC) and infrared absorption spectroscopy (IR) data
  • DSC measures thermal transition temperatures at which a crystal absorbs or releases heat when its crystal structure changes or it melts MP data and DSC thermal transition temperatures are typically reproducible within about 1 or 2°C on successive analyses
  • IR measures absorption of infrared light that is associated with the presence of particular chemical bonds that are associated with groups, e g , hydroxyl, that vibrate in response to particular light wavelengths
  • BrEA hemihydrate which is typically substantially free of other forms of BrEA, such as amorphous BrEA or anhydrous BrEA
  • BrEA hemihydrate or crystalline BrEA hemihydrate refers to solid BrEA and water having an ordered arrangement of substantially all of the constituent molecules in a defined three-dimensional spatial pattern or lattice Crystalline BrEA hemihydrate may comprise one or more crystal habits, e g , tablets, rods, plates or needles
  • BrEA hemihydrate that is substantially free of other forms of BrEA means a dry or substantially dry (where a I ⁇ qu ⁇ d(s) comprises less than about 10% w/w of the total weight) solid preparation where more than about 55% w/w of the BrEA in the preparation is present as BrEA hemihydrate
  • Such compositions typically comprise at least about 60% w/w, or at least about 70% w/w or at least about 80% w/w usually at least about 90% w
  • BrEA hemihydrate may conveniently be identified by reference to BrEA hemihydrate characterized by one or more of (1 ) its melting or decomposition point or range (optionally expressed as +/- 2°C), (2) one or more BrEA hemihydrate DSC transition temperatures or ranges (any of which may be optionally expressed as +/- 2°C), (3) one or more characteristic BrEA hemihydrate IR absorption bands, (4) 1 , 2, 3, 4, 5, 6 or more of the highest intensity XRD peaks (any one or more of which are optionally expressed as +/- 0 1° Theta or +/- 0 2° Theta) obtained from an XRD spectrum of BrEA hemihydrate using Cu-K ⁇ radiation (e g , obtained essentially according to the method described at U S Pharmacopoeia, volume 23, 1995, ⁇ 941 >, p 1843-1845), (5) the presence of less than about 3% or less than about 2% w/w of other compounds, (6) a water content of dry
  • BrEA hemihydrate may be characterized by or one or more of its IR absorption bands, e g , the carbonyl peaks at 1741 cm 1 and 1752 cm and either its melting or decomposition point or range and/or 1 2, 3, 4, 5, 6 or more of the XRD peaks (usually the highest intensity peaks) at Theta (X-ray diffraction angle) values of 17 8, 23 8, 24 2, 26 9-27 2, 28 6, 30 1 and 32 2
  • BrEA hemihydrate is suitable to prepare compositions comprising an exc ⁇ p ⁇ ent(s) suitable for human pharmaceutical use or for veterinary use
  • Such compositions are used to prepare formulations and unit dosages
  • Unit dosages typically comprise tablets, capsules, lozenges or sterile solutions, including sterile solutions for parenteral administration
  • Solid unit dosage forms typically comprise about 5-1000 mg of BrEA hemihydrate, typically about 20-400 mg, e g , about 25 mg, about 50 mg about 100 mg, about 150 mg or about 250 mg per unit dose
  • the invention provides a method to make BrEA hemihydrate comprising contacting water, 16 ⁇ -bromo-3 ⁇ -hydroxy-5 ⁇ -androstan-17-one and a C1-C6 alcohol (e g methanol, ethanol propanol isopropanol butanol) and water Typically the only one C1 -C6 alcohol is present, e g , ethanol, which is anhydrous or which may comprise up to about 2% w/
  • a related embodiment comprises a method to prepare BrEA hemihydrate comprising precipitating BrEA from a solution comprising at least about 15-25% w/w water, about 35-45% w/w of a BrEA preparation and at least about 35-45% w/w of one or more water-miscible solvents, typically Ci s alcohols (methanol, ethanol, propanol, isopropanol, butanol)
  • the BrEA preparation may optionally comprise one or more by-products of BrEA synthesis
  • Typical BrEA hemihydrate preparations or batches comprise less than about 5% w/w, usually less than about 3% or about 2% w/w of other compounds, such as byproducts of BrEA synthesis
  • aspects of this method include contacting water with an organic solution that comprises BrEA and an organic solvent such as a C1-C6 alcohol
  • BrEA hemihydrate Solutions that contain BrEA hemihydrate crystals or precipitate are invention embodiments that are used to prepare solid BrEA that is later dried and stored, typically at ambient temperatures
  • Precipitation of BrEA hemihydrate from water-containing solutions is accomplished by known methods, e g , reducing the solution's temperature, using saturated or nearly saturated BrEA solutions, vacuum concentration of saturated or nearly saturated BrEA solutions (which is typically conducted at a relatively low temperature, usually about 15- 25°C), seeding with saturated or nearly saturated BrEA solutions with BrEA hemihydrate crystals (e g , about 10-100 mg per 1 -10 L of solution), by heating a saturated or nearly saturated BrEA solution (about 25-35°C for a few minutes followed by allowing the temperature to fall or by actively cooling the solution) and optionally see ⁇ mg the solution with BrEA hemihydrate crystals or by addition of a liquid,
  • Other related embodiments comprise a product produced by the process of contacting a solution comprising BrEA and an organic solvent with water
  • the solutions are as described above, e g , a solution comprising about 3-5% v/v water and at least about 40% v/v of one or more water-miscible solvents, typically polar solvents such as Ci 6 alcohols or ketones (e g , methanol, ethanol, propanol, isopropanol, butanol, typically ethanol or acetone)
  • polar solvents such as Ci 6 alcohols or ketones
  • Such processes are accomplished by any one or more of the techniques described in the paragraph above, e g , cooling of a saturated or nearly saturated BrEA water-ethanol solution and optionally seeding the cooled solution with BrEA hemihydrate
  • An embodiment related to this comprises solutions or solids that comprise wet BrEA hemihydrate crystals or wet filtered or centrifuged BrEA hemihydrate cakes which may be obtained after crystall
  • Formulations will typically be used to prepare unit dosages e g tablets capsules or lozenges for oral buccal or sublmgual administration that comprise about 10- 1000 mg or typically about 25-400 mg of BrEA hemihydrate
  • a product for parenteral (e g , subcutaneous, subdermal, intravenous, intramuscular, intrape ⁇ toneal) administration made by the process of contacting BrEA hemihydrate and a liquid excipient, e g , any one, two, three or more of PEG 100, PEG 200, PEG 300, PEG 400, propylene glycol, benzyl benzoate, benzyl alcohol or ethanol, and optionally sterilizing the solution and optionally dispensing the solution into vials or ampules (typically amber glass), which may be single-use or multi-use and optionally storing
  • parenteral e g , subcutaneous, subdermal, intravenous, intramuscular, intrape ⁇ toneal
  • a liquid excipient e
  • kits include a product produced by the process of contacting BrEA hemihydrate, which may be substantially free of other forms of BrEA, with an excipient suitable for human pharmaceutical use or for veterinary use
  • the product is useful to make formulations or unit dosage forms that contain the hemihydrate
  • Formulations made from or containing BrEA hemihydrate will usually be stored under conditions that limit the amount of water that reaches the formulation, e g , silica gel in a sealed container that holds a formulation
  • Water permeation characteristics of containers have been described, e g , Containers - Permeation, Chapter, USP 23, 1995, U S Pharmacopeial Convention, Inc Rockville, MD, p 1787
  • Embodiments include invention compositions that transiently occur when a method step or operation is performed For example, when a formula 1 compound such as BrEA, containing less than about 3% water is contacted with an excipient, e g , a PEG, an alcohol, propylene glycol or benz
  • formula 1 compound that is present in invention compositions and formulations is completely dissolved in the non-aqueous excipients
  • transient compositions and some formulations the formula 1 compound is partially dissolved while the remaining portion is present as a solid, which can be a suspension or a colloid
  • compositions and formulations suitable for parenteral delivery of formula 1 compounds to humans or animals typically comprise two three or more excipients
  • Exemplary embodiments include (1 ) any two, three or four of propylene glycol, PEG200, PEG300, ethanol and benzyl benzoate and (2) any two, three or four of propylene glycol, PEG100, PEG200, PEG300, PEG400 and benzyl benzoate
  • Invention compositions and formulations generally comprise about 0.01-10% of BrEA, usually about 1 -5%, and about 0 01 -3% water, typically about 0 05-3%, usually about 0 1-1 %
  • the invention formulations are usually presented as unit or multi-unit dosages suitable for parenteral administration once or twice per day or once per 2-3 days.
  • Unit dosages comprise about 3-1000 mg of BrEA per unit dose, typically about 5-500 mg, usually about 10-200 mg
  • a unit dose usually comprises about 10-250 mg of BrEA, usually about 100-200 mg, in a volume of about 1-6 mL, usually about 2-4 mL
  • Invention embodiments include the product made by a process of combining, mixing or otherwise contacting BrEA and one, two or more excipients Such products are produced by routine methods of contacting the ingredients Such products optionally also contain a diluent, a disintegrant and a binder, or other excipients described herein or in references cited herein
  • Invention embodiments include compositions that comprise less than about 3% water, a formula 1 compound and a compound that is not generally considered suitable for human use but is useful to make an invention formulation for veterinary use
  • Veterinary formulations are compositions useful for the purpose of administering invention compositions to primates, cats, dogs, horses cows, rabbits and other subjects and may contain excipients acceptable in the veterinary art and are compatible with formula 1 compounds such as BrEA
  • These veterinary compositions may not always be suitable for human use because they contain an excipient that is not suitable for human use, e g , an alcohol other than ethanol such as methanol propanol or butanol Typically such excipients will be present at relatively low levels e g , about 1 -30%, usually about 1-5%
  • Invention embodiments include compositions and formulations e g , unit dosage forms and sterile solutions, that comprise (1 ) about 1 -100 mg/mL of a formula 1 compound(s), about 57 5% propylene glycol,
  • invention compositions or formulations e g , unit dosage forms, any of embodiments (1)-(14) above, or compositions used to make formulations, at about 10-40°C for at least about 3 days, e g , storage at ambient temperature for about 1-24 months
  • Invention formulations will typically be stored in hermetically or induction sealed containers for these time periods
  • Invention compositions will typically be held in closed containers
  • the specification and claims disclose exemplary suitable formulations and unit dosage forms for these embodiments
  • R 1 -R 6 , R 0 R 15 , R 7 and R 18 comprise an ammo acid or a peptide e g
  • R 1 , R 2 or R 4 comprises an am o acid or a peptide
  • R 3 is a halogen and R 5 and R 6 are both -CH 3
  • the peptide at one or more of R 1 -R 6 can comprise a cell surface binding peptide such as the entire protein or a sequence from fibronectin or retronectm e g KQAGDV
  • each R 4 is independently selected.
  • R 4 is hydrogen and the other is another moiety
  • both R 4 are independently selected moieties other than hydrogen, e g , a C1 to C20 organic moiety
  • R 1 -R 6 , R 10 , R 15 , R 17 and R 18 include moieties, e g , esters, thioesters, carbonates, ammo acids, peptides and/or carbamates, that are chemically and/or enzymatically hydrolyzable, often under physiological conditions
  • Such moieties are independently chosen Typically these moieties will give rise to -OH, -SH or -NH 2 at the R 1 -R 6 positions of the steroid nucleus
  • Embodiments of formula 1 compounds include ones where (1) one of R 1 , R 2 and R 4 is a hydrolyzable moiety (e g , ester, thioester, carbonate, am o acid, peptide or carbamate), the other two of R , R 2 and R 4 are -
  • one or more of R -R 6 , R 10 , R 15 , R 17 and R 18 comprises an ammo acid or a peptide, while the remaining groups are independently selected from the moieties defined herein
  • the peptides are typically dimers (dipeptides) or t ⁇ mers (t ⁇ peptides)
  • one of R 1 , R 2 or R 4 comprises an ammo acid
  • R 3 is a halogen, hydroxyl or an ester
  • R 5 and R 6 independently are -H, -(CH 2 ) n -CH 3 , -(CH 2 ) n -CH 2 OH, or -(CH 2 ) n -CH 2 F, -(CH 2 ) 2 4 -0- (CH 2 ) 2 4 -CH 3 , where n
  • Hydrolyzable moieties typically comprise acyl groups, esters ethers, thioethers, amides, ammo acids, peptides, carbonates and/or carbamates
  • these moieties contain a total of about 4 to about 10 carbon atoms
  • These hydrolyzable moieties in other embodiments comprise an organic moiety as described above for ester, that contains 2, 3, 4, 5, 6, 7 8, 9, 10, 11 or 12 carbon atoms and 1 , 2, 3, 4, 5 or 6 heteroatoms, e g , oxygen, nitrogen or sulfur
  • These hydrolyzable moieties can comprise no groups that are charged in plasma, blood, intracellular cytoplasm or in the gut, or they can comprise 1 , 2, 3 or more positive, negative or positive and negative charges under one or more of these conditions The charges may be fractional depending on the group and the conditions it is under
  • These hydrolyzable moieties may comprise 1 2 3, 4 or more substitutions at a hydrogen atom(s)
  • R 24 are -H, -CH 3 , -C 2 H 5 , -CH 2 -d-5 optionally substituted alkyl, -CH 2 CH 2 -d-- 4 optionally substituted alkyl and -CH 2 CH 2 -0-Ci , optionally substituted alkyl R 25 independently is -H, -CH 2 -C 6 H 5 , -CH 2 CH 2 -C 6 H5, d.
  • R 25 are -H, -CH 3 , -C 2 H 5 , -C 3 H / , -C Hg, -dH 13 , -dHs, -C 6 H OH, -C6H 4 OCH 3 , -C6H 4 F, -CH 2 -C ⁇ 5 optionally substituted alkyl, -CH 2 CH 2 -C 1 4 optionally substituted alkyl and -CH 2 CH 2 -0-C ⁇ 4 optionally substituted alkyl
  • Embodiments of formula 1 compounds include or exclude any subset of compounds within the definition of formula 1 , provided that at least one compound remains
  • a subset of formula 1 compounds that are usually included, for example in the invention nonaqueous formulations and in the invention intermittent dosing protocols and immune modulation methods are formula 1 compounds where R 2 is hydroxyl or a group that can hydrolyze to hydroxyl, in either configuration and R 5 and R 6 are methyl in the ⁇ -configuration
  • a subset compounds that are optionally excluded from formula 1 compounds comprises one or all compounds that are disclosed in one or more prior art references or publications, e g , one or more compounds that are disclosed in one or more of the references cited herein, especially for those compounds that can render any claim or embodiment unpatentable for novelty, obviousness and/or inventive step reasons
  • Exemplary embodiments include the formula 1 compounds named according to the compound structure designations given in Tables A and B below Each compound named in Table B is depicted as a compound having formula B
  • R 5 and R 6 are both -CH 3 , there is no double bond at the 1-2-, 4-5- or 5-6-pos ⁇ t ⁇ ons, one R 4 is hy ⁇ rogen, R 7 , R 8 and R 9 are all -CH 2 - and R , R 2 , R 3 and R 4 are the substituents designated in Table A
  • group 1 compounds
  • 5.4.1.7, 5.4.1.8, 5.4.1.9 5.4.1.10, 5.4.2.1 , 5.4.2.2. 5.4.2.3, 5.4.2.4, 5.4.2.5, 5.4.2.6, 5.4.2.7, 5.4.2.8, 5.4.2.9, 5.4.2.10, 5.4.3.1, 5.4.3.2, 5.4.3.3, 5.4.3.4. 5.4.3.5. 5.4.3.6, 5.4.3.7, 5.4.3.8, 5.4.3.9, 5.4.3.10, 5.4.4.1, 5.4.4.2. 5.4.4.3, 5.4.4.4, 5.4.4.5, 5.4.4.6, 5.4.4.7, 5.4.4.8, 5.4.4.9.
  • Additional exemplary formula B compound groups include the following compound groups disclosed below. Unless otherwise specified, the configurations of all hydrogen atoms and R groups for the following compound groups are as defined for the group 1 compounds of formula B above.
  • Group 2 This group comprises compounds named in Table B having R 1 , R 2 , R 3 and R 4 substituents defined in Table A wherein the R 1 , R 2 , R 3 and R 4 substituents are bonded to the steroid nucleus described for group 1 compounds, except that a double bond at the 5-6 position is present.
  • group 2 compound 1.3.1.1 has the structure
  • Group 3 This group comprises compounds named in Table B having R 1 , R 2 , R 3 and R 4 substituents defined in Table A wherein the R 1 , R 2 , R 3 and R 4 substituents are bonded to the steroid nucleus as described for group 1 compounds, except that double bonds at the 1 -2- and 5-6 positions are present.
  • group 3 compound 2.2.5.1 has the structure
  • Group 4 This group comprises compounds named in Table B having R 1 , R 2 , R 3 and R 4 substituents defined in Table A wherein the R 1 , R 2 , R 3 and R 4 substituents are bonded to the steroid nucleus described for group 1 compounds, except that a double bond at the 1-2 position is present
  • group 4 compound 5 2.7 8 has the structure
  • Group 5 This group comprises compounds named in Table B having R 1 , R 2 , R 3 and R 4 substituents defined in Table A wherein the R , R 2 , R 3 and R 4 substituents are bonded to the steroid nucleus described for group 1 compounds, except that a double bond at the 4-5 position is present
  • group 5 compound named 3 5.2 9 has the structure
  • Group 6 This group comprises compounds named in Table B having R 1 , R 2 , R 3 and R 4 substituents defined in Table A wherein the R 1 , R 2 , R 3 and R 4 substituents are bonded to the steroid nucleus described for group 1 compounds, except that double bonds at both the 1 -2 and 4-5 positions are present
  • the group 6 compound named 10.2 7 8 has the structure
  • Groups 7-1 through 7-6 These groups comprise the 6 compound groups described above, except that R 5 is hydrogen instead of methyl
  • group 7-1 has the same steroid nucleus as group 1 above, i e , no double bond is present, but R 5 is -H
  • Group 7-2 comprises the same steroid nucleus as group 2 above, i e , a double bond is present at the 5-6-pos ⁇ t ⁇ on, but R 5 is -H
  • Compound groups 7-3 through 7-6 are assigned a steroid nucleus in the same manner
  • the group 7-1 through group 7-6 compounds named 1 2 1 9 have the structures
  • Groups 8-1 through 8-6 These groups comprise each compound named in groups 1-6, except that R 5 of formula B is -CH 2 OH instead of methyl
  • the groups 8-1 through group 8-6 compounds have structures that are named in the same manner as group 1-6 compounds, except that -CH 2 OH instead of methyl is present at R 5
  • groups 7-1 through 7-6 Thus, group 8-1 and group 8-2 compounds named 1219 have the structures
  • Groups 9-1 through 9-6 comprise each compound named in compound groups 1-6, except that R 6 of formula B is hydrogen instead of methyl-
  • the groups 9-1 through group 9-6 compounds have structures that are named in the same manner as group 7-1 through 7-6 compounds, except that -H instead of methyl is present at R 6 .
  • group 9-1 and group 9-2 compounds named 1.2.1.9 have the structures
  • Groups 10-1 through 10-6 These groups comprise each compound named in compound groups 1 -6 where R 6 of formula 1 is -CH 2 OH instead of methyl.
  • group 10-6 compounds have structures that are named in the same manner as group 7-1 through 7-6 compounds, except that -CH 2 OH instead of methyl is present at R 6 .
  • group 10-1 and group 10-2 compounds named 1.2.1.9 have the structures
  • Groups 11 -1 through 11 -10-6 comprise each compound named in compound groups 1 through 10-6 where R 1 substituents 1 -10 listed in Table A are replaced with the following substituents:
  • group 11-1 through group 11-6 compounds have structures that are named in the same manner as group 7-1 through 7-6 compounds, except that substituents 1-10 of table A are replaced by the substituents 1-10 at R 1 listed above
  • group 11-1 and 11- 2 compounds named 1.2.19 have the structures
  • Group 11-7-1 and 11-7-2 compounds named 1219 have the structures
  • Groups 12-1 through 12-10-6 comprise each compound named in groups 1 through 10-6 where R 1 substituents 1 -10 listed in Table A are replaced with the following groups
  • Groups 13-1 through 13-10-6 comprise each compound named in groups 1 through 10-6 where R 1 substituents 1 -10 listed in Table A are replaced with the following groups
  • Groups 14-1 through 14-10-6 comprise each compound named in groups 1 through 10-6 where R 1 substituents 1 -10 listed in Table A are replaced with the following groups 1 -0-CH 2 C 6 H 5 2 -0-CH 2 C 6 H 5
  • Groups 15-1 through 15-10-6 comprise each compound named in groups 1 through 10-6 where R 1 substituents 1-10 listed in Table A are replaced with the following groups
  • Groups 16-1 through 16-10-6 comprise each compound named in groups 1 through 10-6 where R substituents 1 -10 listed in Table A are replaced with the following groups
  • A6-NH 2 is a 6 carbon alkyl group substituted with -NH 2
  • A8-NH 2 is a 8 carbon alkyl group substituted with -NH 2
  • A4-OH is a 4 carbon alkyl group substituted with -OH or -O-
  • A6-OH is a 6 carbon alkyl group substituted with -OH or -O- 6 -0-C(0)-A8-OH
  • A8-OH is a 8 carbon alkyl group substituted with -OH or -O-
  • Groups 17-1 through 17-10-6 comprise each compound named in compound groups 1 through 10-6 where R 1 substituents 1-10 listed in Table A are replaced with the following groups
  • Groups 18-1 through 18-10-6 comprise each compound named in groups 1 through 10-6 where R 4 substituents 1 -10 listed in Table A are replaced with the following groups 1 -0-C(0)CH 2 NH 2
  • Groups 19-1 through 19-10-6 comprise each compound named in compound groups 1 through 10-6 where R 4 substituents 1 -10 listed in Table A are replaced with the following groups
  • Groups 20-1 through 20-10-6 comprise each compound named in groups 1 through 10-6 where R 4 substituents 1 -10 listed in Table A are replaced with the following groups
  • Groups 21 -1 through 21 -10-6 comprise each compound named in compound groups 1 through 10-6 where R 4 substituents 1 -10 listed in Table A are replaced with the following groups 1 -0-C(S)-0-CH 3 2 -0-C(S)-0-CH 2 CH 3
  • Groups 22-1 through 22-10-6 comprise each compound named in compound groups 1 through 10-6 where R 2 substituents 1 -10 listed in Table A are replaced with the following groups:
  • Groups 23-1 through 23-10-6 comprise each compound named in compound groups 1 through 10-6 where R 3 substituents 1-10 listed in Table A are replaced with the following groups:
  • Groups 24-1 through 24-10-6 comprise each compound named in compound groups 1 through 10-6 where R 2 substituents 1 -10 listed in Table A are replaced with the following groups' 1 -0-C(0)-0-C 6 H 5
  • Groups 26-1 through 26-25-10-6 comprise each compound named in compound groups 1 through 25-10-6 wherein R 7 in formula B is -0-, instead of -CH 2 -
  • R 7 in formula B is -0-, instead of -CH 2 -
  • the 26-1 and 26-2 compounds named 1 2 5 9 have the structures
  • Groups 27-1 through 27-25-10-6 comprise each compound named in compound groups 1 through 25-10-6 wherein R 8 in formula B is -O-, instead of -CH 2 -
  • R 8 in formula B is -O-, instead of -CH 2 -
  • group 27-2 compound 1259 The group 27-8-1 and group 27-8-2 compounds named 1259 have the structures 27-8-1 compound 1.2.5.9, and
  • Groups 28-1 through 28-25-10-6 comprise each compound named in compound groups 1 through 25-10-6 wherein R 9 in formula B is -0-, instead of -CH 2 - and no double bond is present at the 1 -2 position
  • R 9 in formula B is -0-
  • no group 28-3, 28- 4, 28-6, 28-8-3, 28-8-4 or 28-8-6 since a 1 -2 double bond is present in these compounds and a ring oxygen at the 2 position would be charged
  • the 28-1 , 28-2 and 28-5 compounds named 1.2 5 9 have the structures 28-1 compound 1.2.5.9, and
  • the group 28-8-1 and group 28-8-2 compounds named 1.2.5.9 have the structures
  • the group 28-1 1 -1 and 28-1 1 -2 compounds named 1 2 5 9 have the structures 28-11-1 compound
  • Groups 29-1 through 29-25-10-6 comprise each compound named in compound groups 1 through 25-10-6 wherein R 7 is -NH-, instead of -CH 2 -
  • the compounds are named as described for compound groups 26-1 through 26-25-10-6
  • Groups 30-1 through 30-25-10-6 comprise each compound named in compound groups 1 through 25-10-6 wherein R 8 is -NH-, instead of -CH 2 - The compounds are named as described for compound groups 26-1 through 26-25-10-6
  • Groups 31-1 through 31-25-10-6 comprise each compound named in compound groups 1 through 25-10-6 wherein R 9 is -NH-, instead of -CH 2 - and no double bond is present at the 1-2 position Thus, there is , e g , no group 31-3, 31-4, 31-6, 31-8-3, 31-8-4 or 31-8-6 The compounds are named as described for compound groups 26-1 through 26-25-10-6
  • Groups 32-1 through 32-25-10-6 comprise each compound named in compound groups 1 through 25-10-6 wherein two of R 7 R 8 and R 9 independently are - NH-, -O- or -S- instead of -CH 2 -
  • the compounds are named as described for compound groups 26-1 through 26-25-10-6
  • Groups 33-1 through 33-25-10-6 comprise each compound named in compound groups 1 through 25-10-6 wherein each of R 7 R 8 and R 9 independently are - NH-, -O- or -S- instead of -CH 2 -
  • the compounds are named as described for compound groups 26-1 through 26-25-10-6 Groups 34-1 through 34-25-10-6.
  • These groups comprise each compound named in compound groups 1 through 25-10-6 wherein R 7 is -S-, instead of -CH 2 -
  • the compounds are named as described for compound groups 26-1 through 26-25-10-6 Groups 35-1 through 35-25-10-6.
  • These groups comprise each compound named in compound groups 1 through 25-10-6 wherein R 8 is -S-, instead of -CH 2 -
  • the compounds are named as described for compound groups 26-1 through 26-25-10-6.
  • Groups 36-1 through 36-25-10-6 comprise each compound named in compound groups 1 through 25-10-6 wherein R 9 is -S-, instead of -CH 2 - and no double bond is present at the 1-2 position There is , e g , no group 36-3, 36-4, 36-6, 36-8-3, 36-8- 4 or 36-8-6 The compounds are named as described for compound groups 26-1 through 26-25-10-6
  • Groups 42-1 through 42-25-10-6 comprise each compound named in all of the compound groups 1 through 36-25-10-6 described above wherein, when hydrogen is present at the 5-pos ⁇ t ⁇ on, it is in the ⁇ -configuration, instead of the ⁇ - configuration as shown in formula B
  • -CH CH 2 CH 3 , -0-C(0)-(CH 2 ) m -(CF 2 ) n -CH 3 , -0-C(0)-(CH 2 ) m -(CF 2 ) n -CF 3 , -0-C(0)-(CH 2 ) m - (CF 2 ) n -CH 2 F, -0-C(0)-0-(CH 2 ) m -(CF 2 ) n -CH 3 , -0-C(0)-0-(CH 2 ) m -(CF 2 ) n -CF 3 , -0-C(0)-0- (CH 2 ) m -(CF 2 ) n -CH 2 F, -0-C(0)-NH-(CH 2 ) m -(CF 2 ) n -CH 3 , -0-C(0)-NH-(CH 2 ) m -(CF 2 ) n -CF 3 , -O- C(0)-NH-(CH 2 )
  • R 1 -R 2 and R 4 -R 6 comprise one or more of these substituents (or others described herein), the substituent is present in the ⁇ - configuration, while R 3 typically comprises a substituent in the ⁇ -configuration.
  • R 2 is in the ⁇ -configuration
  • one or more of R 1 -R 6 , R 10 , R 15 , R 17 and R 18 independently comprise a nucleoside, a nucleotide, an oligonucleotide or an analog of any of these moieties Typically such moieties are linked to the steroid nucleus through a terminal hydroxyl, thiol, acyl moiety or amine at the 5', 3' or 2' positions, when a hydroxyl, thiol, acyl moiety or amine is present at that position
  • the linkage to the steroid occasionally is through a sugar hydroxyl at an internal 2' position
  • Analogs of phosphodiester linkages include phosphorothioate linkages and others as described in the cited references
  • Oligonucleotide coupling groups means any moiety suitable for generating a phosphodiester linkage or phosphodiester analog linkage between adjacent nucleotides or
  • Table 2 shows these and other exemplary moieties that one or more of R 1 -R 6 , R 0 , R 15 , R 17 and R 18 independently can comprise Pr means a protecting group
  • R 1 -R 6 , R 0 , R 15 , R 17 and R 18 independently can comprise Pr means a protecting group
  • These moieties are often bonded to one or more of the R ' , R 2 and R 4 positions, usually to one or two of those positions
  • a given variable, e g , X in structure A3 or A5 each is independently selected TABLE 2
  • n 0.1.2.3.4.5.6
  • Typical containers for storage of the invention compositions and formulations will limit the amount of water that reaches the materials contained therein Typically, formulations are packaged in hermetically or induction sealed containers
  • the containers are usually induction sealed Water permeation characteristics of containers have been described, e g , Containers-Permeation, chapter USP 23 ⁇ 671>, United States Pharmacopeial Convention Inc 12601 Twinbrook Parkway, Rockville, MD 20852, pp 1787etseq (1995)
  • the use of formula A compounds for treatment of certain diseases, e.g., infections such as malaria, HCV or Cry tospondium, has been described.
  • Formula A compounds have the structure
  • Q is -C(R ⁇ ) 2 - or -C(O)-
  • Q 2 is -C(R ) 2 -, -CfRiHY)-
  • Q 3 is -H or -C R s-
  • Q 5 is or -C(O)-
  • R 3 is d 18 alkyl, C 2 8 alkenyl, C 2 18 alkynyl, a d 18 ester or a d ⁇ 8 thioester, where any of the foregoing d-is or C 2 18 moieties are optionally substituted at one or more hydrogen atoms with one or more independently selected -OR PR , (including -OH), -
  • R 3 is a d 18 fatty acid, C 2 10 alkynyl, (J) n -phenyl-d 5-alkyl, (J) n -phenyl-C 2 5 -alkenyl
  • R 4 is -H a protecting group, optionally substituted Ci 18 alkyl, optionally substituted d 18 alkenyl, optionally substituted d 18 alkynyl, optionally substituted aryl optionally substituted aryl-d- 6 alkyl, optionally substituted aryl-C 2 6 alkenyl, optionally substituted aryl-C 2 6 alkynyl, optionally substituted heterocycle-d e alkyl, optionally substituted C 2 6 alkenyl- heterocycle, optionally substituted C 2 6 alkenyl- heterocycle, optionally substituted C 2 6 alkynyl-heterocycle or an optionally substituted heterocycle, where any of the foregoing moieties
  • Intermittent dosing methods One can intermittently administer the formula 1 compound(s), e g , BrEA or a BrEA ester, to a subject without some of the undesired aspects normally associated with discontinuous dosing Such undesired aspects include development of resistance of a pathogen (virus such as HIV or a parasite such as a Plasmodium parasite) to the therapeutic agent or failure of the patient or subject to adhere to a dosing regimen
  • Intermittent dosing protocols include administration of a formula 1 compound e g orally topically or parenterally as follows (1 ) dosing for about 3 to about 20 days (2) no dosing of the formula 1 compound for about 4 to about 20 days, (3) dosing for about 4 to about 20 days and (4) optionally repeating the dosing protocol 1 2, 3 4 5 6 10 15 20 30 or more times Often the dosing of steps (1 ) and (3) will be maintained for about 3-15 days, usually about 3-5 days In general, steps (1 )-(3) of the dosing protocol
  • the formula 1 compound(s) can be administered by any suitable route, e g , intramuscular (i m or I M ), subcutaneous (s.c. or S C ), intravenous (i v or I V ), intradermal, other parenteral route, aerosol using about 0.1 to about 10 mg/kg/day, usually about 0 2-4 mg/kg/day Alternatively, one can administer the formula 1 compound(s) orally using about 4 to about 40 mg/kg/day, usually about 6-20 mg/kg/day
  • the intermittent dosing methods exclude dosing protocols that are commonly used to deliver contraceptive steroids to, e g , human females, such as daily dosing for 21 days, followed by no dosing for 7 days
  • the non-aqueous formulations described herein that contain formula 1 compound(s) are administered i m or s c
  • aqueous formulations that contain formula 1 compound(s) is administered by i v , i
  • One aspect of invention intermittent dosing is monitoring the subject's response to dosing
  • a subject who has a viral infection e.g., HCV, HIV, SIV, SHIV
  • dosing can be continued for one, two or three additional days, followed by discontinuing the dosing for at least one day (at least 24 hours), usually for at least 2 or 3 days
  • the subject's response shows signs of remission (e g , viral serum RNA begins to increase)
  • dosing can be resumed for another course
  • An aspect of the subject's response to formula 1 compound(s) is that the subject may show a measurable response within a short time, usually about 5-10 days, which allows straightforward tracking of the subject's response, e g , by monitoring viral titer in peripheral white blood cells ("PBMC”) or by measuring viral nucleic
  • prolonged beneficial effects or a sustained immune response by a subject may result from a single administration or a few daily administrations of the formula 1 compound for from intermittent treatment with the formula 1 compound
  • a single administration means that a formula 1 compound is administered to the subject in one, two, three or more doses within a 24 hour period and no further administration of any formula 1 compound to the subject occurs for at least about 45 days to about 2 months, e g , for 3, 4, 5, 6 or more months
  • Prolonged beneficial effects or immune responses may also persist after a short course of treatment has been completed (e g , daily dosing for 2, 3, 4, 5 or 6 days) and the subject is no longer receiving any formula 1 compound, or, in some cases, any other therapeutic treatment to treat the primary cause of the subject s pathological condition
  • Such beneficial effects can persist for more than about 5-30 days
  • a formula 1 compound provides a method to effectively protect a subject against progression of an infection or against adverse consequences of unwanted immune reactions (e g , inflammation) or against immunosuppression (from infection, chemotherapy, etc), without any dosing of the compound for at least 3 months after an initial dosing protocol, which could be an intermittent or a continuous dosing protocol over, e g , 1 day to about 4 months (1-15 days, about 1 month, about 2 months, etc)
  • R 5 -R 9 are as defined for formula 1 compounds
  • R 5 and R 6 are both -CH 3 in the ⁇ -configuration
  • R 7 , R 8 and R 9 are all -CH 2 - H at the 9 and 14 positions are in the ⁇ -configuration
  • acetate at the 3- position is in the ⁇ -configuration
  • H at the 8 position is in the ⁇ -configuration
  • the first compound in scheme 1 is DHEA acetate
  • the acetate groups at the 3, 7, 16, 17 or other positions in this scheme and in other schemes disclosed herein may independently be other ester moieties as described herein, e g , C 2 50 esters including -C(O)-(CH 2 ) 0 4 -(CF 2 ) 0 4 -CF 3 , including -C(0)-CF 3 , -C(0)-C 2 29 optionally substituted alkyl, -C(0)-CH 2 -C 2 28 optionally substituted alkenyl, -C(0)
  • LDA lithium dnsopropyl amide
  • MCPBA m-chloroperbenzoic acid
  • TMSCI t ⁇ methychlorosilane
  • DMAP 4-d ⁇ methylam ⁇ nopyr ⁇ d ⁇ ne
  • Dibromantin 1 ,3-d ⁇ bromo-4,4- dimethylhydantoin
  • Scheme 6 Formula 6 compounds are prepared by treatment of the acetate with lithium acetylide as in Schemes 1 , 2, 3 or 4 R and R A are as defined in Schemes 1 and 2
  • Scheme 7 Formula 7 compounds are prepared from the 3-acetate with reagents described in Schemes 1 and 4 R and R A are as defined in Schemes 1 and 2
  • esters of formula 1 - 10c compounds, such as -0-C(0)-R B where R B is a d-so organic moiety, are prepared from the steroid alcohol by treatment with the appropriate acid anhydride or acid chloride (R B -C(0)- Cl) to form any desired ester Ethers, such as -0-R B , are prepared from alcohols by formation of the alkaline metal alkoxide (Na + or K + ) followed by treatment with a primary or secondary iodide (R B -I) Thionoesters, R B -C(S)-0-, are prepared by treating the R B -C(0)- O- ester with Lawesson's reagent
  • Sulfates NaO-S(0)(0)-0-, R B -0-S(0)(0)-0-, e g , CH 3 (CH 2 ) 0 18 -S(O)(O)-O-, are prepared by treatment of alcohols with chlorosulfonic acid followed by NaOH or alternatively by oxidation of sulfites using KMn0 4 If the alkyl (e g , methyl) ester is desired alkylchloro-sulfonate (methylchloro-sulfonate) can be used Sulfites HO-S(0)-0- and ammonium salts NH 4 0-S(0)-0, or R B 0-S(0)-0- esters (e g , CH 3 O-S(O)-O-) are prepared by standard methods The ammonium salts are prepared by treatment of alcohols with ammonia and sulfur dioxide The esters such as alkyl, alkenyl and alkynyl esters (e g , methyl ester) are obtained when alcohols
  • R B 0-P(SR PR )(0)-0- are generated by treatment of alcohols with the monothio analog of diethylchlorophosphate as described for phosphoesters yielding the phosphothioesters Carbonates
  • R B 0-C(0)-0- are generated from the corresponding steroid alcohol using the chioroformate (R B -C(0)-CI), e g , d 20 alkyl, alkenyl or alkynyl chloroformates (e g CH 3 (CH 2 ) 0 5 -C(0)CI) Carbamates
  • Ammoacid esters, ZNX-CHY-C(0)-0- are generated by coupling the steroid alcohol with the acid chloride of the N-protected ammo acid
  • Oxidation of hydroxyl groups that are linked to the steroid nucleus is used to obtain ketones and related functionalities
  • conversion of alcohols to ketones can be achieved using a variety of oxidizing agents such as Cr0 3 in AcOH, or py ⁇ dinium cholorchromate, py ⁇ dinium dichromate or oxalyl chloride with t ⁇ ethylamine (Swern oxidation)
  • thiols -SH are prepared from alcohols by conversion of the alcohol with inversion to the bromide using PBr 3
  • Treatment of the bromide with thiourea followed by NaOH gives the thiol Thioethers, R B -S-, are prepared from thiols by treatment with NaOH and the required halide, e g , alkyl halide
  • alcohol derivatives like tosylates or mesylates can be displaced by thiolate anions, R B -S , to yield the thioether Thioesters R-C(0)-S-, are prepared by treating the tosylate (mesylate) of the alcohol with the sodium salt of the thioacid
  • Substitution of hydroxyl groups can be used to generate both esters R B 0-C(0)- and amides, NHR B -C(0)-, linked to the steroid at carbon atoms
  • R B is -H, a protecting group or a Ci 50 organic moiety
  • the cyanide group can be hydrolyzed to the amide or the acid
  • the acid is esterified or treated by standard peptide coupling reactions with an O-protected ammo acid in the presence of a suitable carboxyl activating agents such as dicyclohexylcarbodnmide (DCC) to form steroid -C(0)-NH-CHY- C(0)-OR, where Y is the side chain of an ammo acid or a C1-C10 organic moiety and R is a protecting group (or hydrogen when deprotected)
  • DCC dicyclohexylcarbodnmide
  • Amines and derivatives of amines are typically prepared by standard methods
  • amines NH -stero ⁇ d
  • amines are generally prepared using the Hoffmann rearrangement (Br 2 , NaOH) from the amide (NH 2 -C(0)-stero ⁇ d) or the Curtius rearrangement (NaN 3 ) from the acid chloride of the steroid
  • the R B substituent can subsequently be introduced by alkylation
  • Steroid alcohols can be used as starting materials under standard Mitsunobu conditions (PPh 3 , DEAD) to yield N-Boc sulfonamides using N-(t-butoxycarbonyl)-p-toluenesulfonam ⁇ de
  • One can selectively remove either protecting group Treatment with t ⁇ fluoroacetic acid affords the sulf
  • Amines (NH 2 -stero ⁇ d) can be converted to amides (R B NH-C(0)-stero ⁇ d) using acyl chlorides (R B -C(0)-CI) Treatment with ethyl chloroformate gives the N-carbamate (R B 0- C(O)-NH-stero ⁇ d)
  • the amine (NH 2 -stero ⁇ d) can be alkylated with an ⁇ -bromoester (R B - C(0)-CHY-NH 2 ) to yield the amio acid substituted steroid (R B -0-C(0)-CHY-NH-stero ⁇ d)
  • the desired intermediate is optionally separated from other products or at least partially enriched (e g., enriched at least about 10-fold, usually at least about 50-100-fold) from other products before subsequent reactions are conducted
  • Substitution at steroid carbon atoms will generally proceed with greatest efficiency at the 3-pos ⁇ t ⁇ on, which is relatively ste ⁇ cally unhindered and C-17 is generally somewhat less accessible than the C-3 position
  • the relative reactivities of the C-3, C-7, C-17 and C-16 positions allows one to use their reactivities to control the sequential introduction of different functional groups into the same steroid molecule
  • groups, such as hydroxyl at more reactive positions, C-3 or C-17 may be sequentially protected or deprotected to allow introduction of functional groups at other positions, such as C-7 or C-16
  • Polymers such as PEG are linked to the compounds essentially as described above
  • PEG200 or PEG300 is linked to the steroid at the 3, 7, 16, 17 or other positions by an ether linkage (PEG-O-steroid) using a PEG alkoxide (PEG-ONa), to displace the steroid bromide
  • PEG-Br can be treated with the steroid alkoxide
  • Polyethylene glycol esters such as those described in U S patent 5681964 can also be prepared using a suitable formula 1 compound and the methods described therein Monosaccha ⁇ des or polysaccharides and oligonucleotides are linked to steroid hydroxyl groups using known methods, see e g , U S patent 5627270
  • Formula 1 steroid analogs that comprise one or more ring heteroatoms are synthesized according to the following methods Scheme 11
  • Scheme 11 Formula 1 compounds that comprise two or three ring heteroatoms are prepared as shown in the schemes.
  • X is -CH 2 -, -NH-, -O-, or -S-
  • R 40 is -H or -Br
  • R 41 is an organic moiety having about 12 carbon atoms or less, typically C1 - C8 optionally substituted alkyl (e.g., methyl, hydroxymethyl, ethyl, propyl) or C2 - C8 optionally substituted alkenyl having a single double bond (e.g , vinyl) with 1 , 2, 3 or more indepenently selected substituents (e.g., -OH, -COOH, -O-) and with any substituents that comprise a functional group generally being protected.
  • substituents e.g., -OH, -COOH, -O
  • Preparation of compound 20 from 19 is accomplished using a glycol such as HOC(CH 3 ) 2 C(CH 3 ) 2 OH in acid (H + ) (B.H. Lipshutz et al., Synth Commun. 12. 267, 1982).
  • a glycol such as HOC(CH 3 ) 2 C(CH 3 ) 2 OH in acid (H + ) (B.H. Lipshutz et al., Synth Commun. 12. 267, 1982).
  • H + HOC(CH 3 ) 2 C(CH 3 ) 2 OH in acid
  • Scheme 13 The scheme and rections shown below are used to prepare the compound of structure 1_3 and related compounds that are used to introduce oxygen, carbon, nitrogen or sulfur into the R 7 and R 8 positions of formula 1 compounds.
  • the reactant in the preparation of compound 63, 3-chloro-2-methyipropene (reg. No. 563-47- 3), is available commercially (e.g., Aldrich, Fluka)
  • the 11A compounds are deprotected to yield the aldehyde compounds 12
  • the bromine atom is ultimately found at the 7-pos ⁇ t ⁇ on
  • the bromine may be converted to a hydroxyl by reaction of the steroid with base (e g , aqueous KOH), and the hydroxyl may in turn be protected using known methods, e g , using C 6 H 5 -CH 2 -Br and base (KOH)
  • base e g
  • KOH C 6 H 5 -CH 2 -Br and base
  • the alcohol is protected and deprotected essentially using described methods, see, e g , W H Hartung et al , Org React 7 263, 1953, E J Rerst et al , J Org.
  • Various groups that may comprise the formula 1 compounds described herein can contain one or more reactive moieties such as hydroxyl, carboxyl, ammo or thiol intermediates used to make formula 1 compounds may be protected as is apparent in the art Noncyc c and cyclic protecting groups and corresponding cleavage reactions are described in "Protective Groups in Organic Chemistry", Theodora W Greene (John Wiley & Sons, Inc , New York, 1991 , ISBN 0-471-62301-6) (hereafter "Greene”) and will not be detailed here
  • these protecting groups are groups that can be removed from the molecule of the invention without irreversibly changing the covalent bond structure or oxidation/reduction state of the remainder of the molecule
  • the protecting group, -R PR that is bonded to an -O
  • Protecting groups commonly are employed to protect against covalent modification of a sensitive group in reactions such as alkylation or acylation Ordinarily, protecting groups are removed by, e g hydrolysis, elimination or aminolysis Thus, simple functional considerations will suffice to guide the selection of a reversible or an irreversible protecting group at a given locus on the invention compounds Suitable protecting groups and criteria for their selection are described in T W Greene and P G M Wuts, Eds "Protective Groups in Organic Synthesis” 2nd edition, Wiley Press at pps 10-142 143-174, 175-223, 224- 276, 277-308, 309-405 and 406-454
  • a group is a protecting group if when, based on mole ratio, 90% of that protecting group has been removed by a deprotection reaction, no more than 50%, typically 25%, more typically 10%, of the deprotected product molecules of the invention have undergone changes to their covalent bond structure or oxidation/reduction state other than those occasioned by the removal of the protecting group
  • the mole ratios are determined when all of the groups of that type are removed
  • each type of protecting group is treated (and the mole ratios are determined) independently or together with others depending on whether the deprotection reaction conditions
  • Dimethylphosphinothioyl, 2,4-D ⁇ n ⁇ tro-phenylsulfenate), and Sulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate, Tosylate (Tos))
  • hydroxy protecting groups include subtituted methyl ethers, substituted benzyl ethers, silyl ethers, and esters including sulfonic acid esters, still more typically, t ⁇ aikylsilyl ethers, tosylates and acetates
  • Typical 1 ,2- and 1 ,3-d ⁇ ol protecting groups are described in Greene at pages 1 18-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1-t- Butylethylidene, 1 -Phenylethyl ⁇ dene, (4-Methoxyphenyl)ethyl ⁇ dene, 2,2,2- T ⁇ chloroethylidene, Acetonide (Isopropyhdene), Cyclopenty dene, Cyclohexylidene, Cycloheptylidene, Benzylidene, p-Methoxybenzylidene, 2,4-D ⁇ methoxybenzyl ⁇ dene, 3,4-D ⁇ methoxybenzyl ⁇ dene, 2-N ⁇ trobenzyi ⁇ dene), Cyclic Ortho Esters (Methoxymethylene, Ethoxymethylene, Dimethoxymethylene, 1 -Methoxyethyl ⁇ dene, 1- Eth
  • 1 ,2- and 1 ,3-d ⁇ ol protecting groups include epoxides and acetonides
  • Typical am o protecting groups are described in Greene at pages 315-385 and include Carbamates (Methyl and Ethyl, 9-Fluorenyimethyl, 9(2- Sulfo)fluoroenylmethyl, 9-(2,7-D ⁇ bromo)fluorenylmethyl, 2,7-D ⁇ -t-buthyl-[9-(10,10- d ⁇ oxo-10,10,10,10-tetrahydroth ⁇ oxanthyl)]-methyl, 4-Methoxy-phenacyl), Substituted Ethyl (2,2,2-T ⁇ choroethyl, 2-T ⁇ methyls ⁇ lylethyl, 2-Phenyiethyl, 1 -(1-Adamantyl)-1- methylethyl, 1 , 1 -D ⁇ methyl-2-haloethyl, 1 , 1 -D ⁇ methyl-2,2-d ⁇ bromoethyl, 1 ,1-D ⁇
  • Phenylbenzoyl Amides With Assisted Cleavage (N-o-Nitrophenylacetyl, N-o- Nitrophenoxyacetyl, N-Acetoacetyl, (N'-D ⁇ th ⁇ obenzyloxycarbonylam ⁇ no)acetyl, N-3-(p- Hydroxyphenyl)prop ⁇ onyl, N-3-(o-N ⁇ trophenyl)prop ⁇ onyl N-2-Methyl-2-(o- n ⁇ trophenoxy)prop ⁇ onyl, N-2-Methyl-2-(o-phenylazophenoxy)prop ⁇ onyl, N-4- Chlorobutyryl, N-3-Methyl-3-n ⁇ trobutyryl, N-o-Nitrocinnamoyl, N-Acetylmethionme Derivative N-o-Nitrobenzoyl, N-o-(Benzoyloxymethyl)benzoyl, 4,5-D ⁇ phen
  • ammo protecting groups include carbamates and amides, still more typically N-acetyl groups
  • Groups capable of biological cleavage typically include prodrugs
  • prodrugs A large number of such groups are described in "Design of Prodrugs", Hans Bundgaard (Elsevier, N Y , 1985 ISBN 0-444-80675-X) (Bundgaard) and will not be detailed here In particular
  • Bundgaard at pages 1 -92 describes prodrugs and their biological cleavage reactions for a number of functional group types Prodrugs for carboxyl and hydroxyl groups are detailed in Bundgaard at pages 3 to 10, for amides, imides and other NH-acidic compounds at pages 10 to 27, amines at pages 27 to 43, and cyclic prodrugs at pages 62 to 70 These moieties are optionally bonded to the steroid at one two or more of R 1 -R 6 , R 10 , R 15 , R 7 and R 18 Metabolites.
  • the invention includes novel and unobvious compounds produced by a process comprising contacting a compound of this invention with a subject, e g , a human, rodent or a primate, for a period of time sufficient to yield a metabolic product thereof
  • a subject e g , a human, rodent or a primate
  • Such products typically are identified by preparing a radiolabeled (e g 14 C, 3 H, 131 1, 32 P, 35 S or "Tc) compound of the invention, administering it parenterally in a detectable dose (e g greater than about 0 5 mg/kg) to an animal such as rat, mouse, guinea pig, primate, or to a human, allowing sufficient time for metabolism to occur (typically about 30
  • formulations and compositions for preparing formulations While it is possible for the active ⁇ ngred ⁇ ent(s) to be administered alone it is usual to present them as pharmaceutical formulations.
  • the formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, i e , a formula 1 compound, together with one or more acceptable excipients therefor and optionally other therapeutic ingredients
  • compositions comprising one or more pharmaceutically acceptable excipients or carriers
  • One or more formula 1 compound(s) are administered by any route appropriate to the condition to be treated
  • Suitable routes for the non-aqueous liquid formulations and other formula 1 compound formulations include oral rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural)
  • the non-aqueous liquid formulations are delivered by a parenteral route
  • the formula 1 compound(s) may be present as a non-aqueous liquid formulation, a dry solid formulation that is an oral, topical, parenteral formulation, or as an aqueous liquid formulation that is used parenterally, orally or topically
  • the preferred route may vary with, for example, the subject's pathological condition or
  • the formulations include those suitable for the foregoing administration routes.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy Techniques, excipients and formulations generally are found in, e g , Remington's Pharmaceutical Sciences, Mack Publishing Co , Easton, PA 1985, 17 th edition Nema et al , PDA J Pharm Sci Tech. 1997 51 166-171
  • Methods to make invention formulations include the step of bringing into association an active ⁇ ngred ⁇ ent(s) with the exc ⁇ p ⁇ ent(s)
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or finely divided solid excipients or both, and then if appropriate, shaping the product
  • Formulations of the invention suitable for oral administration are prepared as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules, as solution or a suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-m-water liquid emulsion or a water-m- oil liquid emulsion
  • the active ⁇ ngred ⁇ ent(s) may also be presented as a bolus, electuary or paste
  • a tablet is made by compression or molding, optionally with one or more accessory ingredients
  • Compressed tablets may be prepared by compressing in a suitable machine the active ⁇ ngred ⁇ ent(s) in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ⁇
  • the formulations are typically applied as a topical ointment or cream containing the active ⁇ ngred ⁇ ent(s) in an amount of for example, 0 075 to 20% w/w (including active ⁇ ngred ⁇ ent(s) in a range between 0 1 % and 20% in increments of 0 1 % w/w such as 0 6% w/w 0 7% w/w, etc ) often 0 2 to 15% w/w and most often 0 5 to 10% w/w
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base Alternatively, the active ingredients may be formulated in a cream with an oil-m-water cream base
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhyd ⁇ c alcohol, i e an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1 ,3-d ⁇ ol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof
  • the topical formulations may desirably include a compound that enhances absorption or penetration of the active ⁇ ngred ⁇ ent(s) through the skin or other affected areas Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs
  • the oily phase of the emulsions of this invention may be constituted from known excipients in a known manner While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil A hydrophihc emulsifier may be included together with a lipophiiic emulsifier, which acts as a stabilizer Some embodiments include both an oil and a fat Together, the emuls ⁇ f ⁇ er(s) with or without stab ⁇ l ⁇ zer(s) make up the so-called emulsifying wax and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween60TM, Span ⁇ OTM, cetostearyl alcohol, benz
  • Creams are generally a non-greasy, non-staining and washable products with suitable consistency to avoid leakage from tubes or other containers
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl my ⁇ state, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used These may be used alone or in combination depending on the properties required Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active mgred ⁇ ent(s) is dissolved or suspended in a suitable exc ⁇ p ⁇ ent(s), especially an aqueous solvent for active ⁇ ngred ⁇ ent(s) that comprise one or more charges at pH values near neutrality, e g , about pH 6-8
  • the active ⁇ ngred ⁇ ent(s) is typically present in such formulations in a concentration of about 0 5-20% w/w typically about 1- 10% w/w often about 2-5% w/w
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth, pastilles comprising the active ⁇ ngred ⁇ ent(s) in an inert basis such as gelatin and glycerin, or sucrose and acacia, and mouthwashes comprising the active ingredient in a suitable liquid exc ⁇ p ⁇ ent(s)
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a sahcylate
  • Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0 01 to 500 microns (including average particle sizes in a range between 0 01 and 500 microns in 0 1 micron or other increments, e g , 0 05, 0 1 , 0 5, 1 , 1 5, 2 0, 2 5, 3 0, 3 5, 4 0, 4 5, 5 0, 6, 7, 8, 9, 10, 20, 25, 30, 35, 50, 75, 100, etc microns), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs
  • Suitable micronized formulations include aqueous or oily solutions or suspensions of the active ⁇ ngred ⁇ ent(s)
  • Formulations suitable for aerosol, dry powder or tablet administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of viral or other infections as described herein Such formulation may be administered, e g , orally, parenterally (i
  • Formulations suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bactenostats and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents
  • the formulations are presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example water for injection immediately prior to use
  • sterile liquid excipient for example water for injection immediately prior to use
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described
  • Unit dosage formulations are those containing a daily dose or unit daily sub-dose, as recited herein or an appropriate fraction thereof, of the active ⁇ ngred ⁇ ent(s)
  • the formulations of this invention may include other agents or excipients conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents
  • the invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary exc ⁇ p ⁇ ent(s) therefor
  • Veterinary excipients are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials that are otherwise inert or acceptable in the veterinary art and are compatible with the active ⁇ ngred ⁇ ent(s)
  • veterinary compositions may be administered orally, parenterally or by any other desired route Invention formulations include controlled release pharmaceutical formulations containing an active ⁇ ngred ⁇ ent(s) ("controlled release formulations") in which the release of the active ⁇ ngred ⁇ ent(s) is controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ⁇ ngred ⁇ ent(s)
  • an effective dose of active ⁇ ngred ⁇ ent(s) depends at least on the nature of the condition being treated, toxicity, whether the compound(s) is being used prophylactically (lower doses) or against an active infection or condition, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies It can be expected to be from about 0 05 to about 30 mg/kg body weight per day
  • the daily candidate dose for an adult human of approximately 70 kg body weight will range from about 1 mg to about 500 mg, generally between about 5 mg and about 40 mg, and may take the form of single or multiple doses or administration sites
  • Embodiments include formulations that comprise a liposome or lipid complex that comprises a formula 1 compound(s), e g , BrEA or an ester, carbamate, carbonate, ammo acid or peptide thereof
  • a formula 1 compound(s) e g , BrEA or an ester
  • carbamate e.g , carbamate
  • carbonate e.g , ammo acid or peptide thereof
  • Such formulations are prepared according to known methods, e g , U S patents 4427649, 5043165, 5714163, 5744158, 578321 1 , 5795589, 5795987,
  • the liposomes optionally contain an additional therapeutic agent(s), e g , amphote ⁇ cin B, cis-platm, ad ⁇ amycin a protease inhibitor, a nucleoside or a nucleotide analog, such as one of those mentioned herein
  • Formulations that comprise liposomes can be delivered to a subject by any standard route, e g , oral, aerosol or parenteral (e g , s c , i v or i m )
  • the formula 1 compounds, or the biologically active substances produced from these compounds by hydrolysis or metabolism in vivo have a number of clinical and non-clinical applications
  • the compounds are generally useful to enhance Th1 immune responses or to reduce Th2 immune responses
  • reference to Th1 or Th2 immune responses means such responses as observed in mammals generally and not as observed in the murine system from which the Th1 and Th2 terminology originated
  • Th1 cells preferentially display chemokme receptors CXCR3 and CCR5
  • Th2 cells preferentially express the CCR4 molecule and a smaller amount of the CCR3 molecule
  • compositions that comprise an amount of at least one formula 1 compound effective to enhance the relative proportion of a desired immune cell subset, e g , CD4 + T cells, NK cells or dendritic cells, or to modulate one or more functions of immune cell subsets and a pharmaceutically acceptable carrier
  • Functions that the formula 1 compounds affected include expression of CD molecules or alteration of the proportion of cell subsets, e g , CD4 + or CD8 + T cells, or their relative numbers in a subject's blood or tissues CD molecules participate in the function of various immune cell subsets and can be useful as markers for immune function in vivo
  • the formula 1 compounds activate immune cells which generally alters (increases or decreases) expression of, or changes the numbers of cells that express combinations of, CD4, CD6, CD8, CD25, CD27, CD28, CD30, CD38, CD39, CD43, CD45RA
  • adhesion molecules CD2, CD5, CD8, CD1 1 a, CD11 b, CD1 1 c, CD18, CD29, CD31 , CD44, CD49a, CD49b, CD49c, CD49d, CD49e, CD49f, CD50, CD54, CD58, CD103 or CD104 are also detectably affected after administration of the formula 1 compounds to a subject Often the numbers of cells that express these molecules are increased, e g , CD5 or CD56
  • the adhesion molecules function in various aspects of immune responses, such as binding to class I MHC molecules, transducing signals between cells or binding to molecules in the extracellular matrix associated with endothelial or other cell types
  • Administration of the formula 1 compounds to a subject also affects the numbers of certain immune cell subsets e g , NK cells (e g , CD8 " , CD56 + or CD8 + , CD56 + ) or lymphokme activated killer cells (LAK) Increased circulating NK or LAK cells are typically observed, which
  • CD62L Expression of one or more homing receptors such as CD62L is may also be detectably affected after administration of the formula 1 compounds to a subject- Often, the numbers of cells that express these molecules are increased, e g , CD62L
  • Other CD molecules that are modulated by the presence of the formula 1 compounds in a subject include cytokme receptor molecules such as CD115, CDW116, CD117, CD118, CDW119, CD120a, CD120b, CD121a, CD121b, CD122, CD123, CD124, CD125 CD126, CDW127, CDW128 or CDW130 Often, the numbers of receptor molecules per cell will be modulated For example receptors for cytokines that mediate Th1 immune responses (e g , IL-2, ⁇ lFN) will typically increase in or on cells that mediate Th1 immune responses Modulation of these molecules may be by direct interactions with a receptor(s) in the cell that expresses the cytok e receptor or indirectly by modulation of cytokme synthesis in
  • Treatment of a subject with a formula 1 compound can result in a change of at least 25-50% above or below (e g , at least 30% or at least 40% above cr below) the control or basal level of some immune cell subsets
  • increases of more than about 30% in the total numbers of activated CD8 + T cells e g , CD8 + , CD69 + , CD25 + T cells, CD8 + , CD69 + , CD25 " T cells or CD8 + , CD69 " CD25 + T cells
  • Such increases may be greater than 50%, 60% or 100% in the total numbers of activated CD8 + T cells or subsets of activated CD8 + T cells in individual subjects
  • Such increases are about in the total numbers of activated CD8 + T cells or subsets of activated CD8 + T cells averages about 30-40%, with individual subjects experiencing increases over 100% in the numbers of activated CD8 + T cells per unit blood volume compared to the basal level
  • the concentration of circulating CD4", CD69 + , CD25 (Th1 helper cells) and CD8 4 , CD16 + , CD38 + LAK cells or CD8 ⁇ CD16 + , CD38 + LAK cells typically increases during or after the course of dosing a subject with a formula 1 compound
  • CD8 , CD16 + , CD38 + and CD8 ⁇ CD16 + , CD38 + (ADCC effector cells) and low side scatter Lin , DR + , CD123 + (dendritic precursors) or low side scatter Lin , DR + , CD11 c + (dendritic cells or precursors) may show modest to significant increases
  • administering results in a favorable shift in the balance of Th1 or Th2 responses the subject can mount in the face of immunosuppression
  • Th1 responses are suboptimal or insufficient
  • treatment with a formula 1 compound results in enhancement of Th1 responses or a reduction in Th2 responses
  • Th2 responses are suboptimal or insufficient
  • treatment with a formula 1 compound results in enhancement of Th2 responses or a reduction in Th1 responses
  • the formula 1 compounds can thus be used to shift the nature of a subject's immune response to result in a more balanced immune response from immunosuppression
  • the compounds can selectively suppress inappropriate or unwanted immune responses Enhanced Th1 responses appears to be at least partly due to one or more of (i) a reduction in biological restraints, e g
  • An aspect of the invention methods is an alteration in the expression of IL-4 or IL- 10 that occurs after administration of a formula 1 compound, e g , BrEA, to a subject
  • a formula 1 compound e g , BrEA
  • extracellular IL-4 or IL-10 levels rapidly decrease to levels that are undetectable by ELISA
  • Intracellular IL-10 levels are reduced to levels that are near or below the limits of detection by flow cytometry
  • the administration of a formula 1 compound to a subject thus provides a means to inhibit either or both of these interleukms
  • Such inhibition may be associated with enhancement of Th1 immune responses relative to Th2 or ThO responses, e g , in subjects where Th1 responses are suppressed (e g , from viral, bacterial or parasite infection (HIV, HCV, etc) or chemotherapy) or are otherwise suboptimal
  • levels of either IL-4 or IL-10, usually IL-10, before dosing with a formula 1 compound is low or undetectable In these
  • the formula 1 compound(s) is administered to a subject who has a pathogen infection, such as a viral bacterial or parasite infection
  • a pathogen infection such as a viral bacterial or parasite infection
  • the formula 1 compounds can be considered for use in a broad scope of infections (see, e g , J B Peter, editor Use and Interpretation of Laboratory Tests in Infectious Disease, 5 th edition, Specialty Laboratories, Santa Monica CA 90404 1998, pages 1 -271 ), since the compounds generally enhance Th1 immune responses and/or reduce Th2 immune responses Difficulty in treating some infections, e g , progressive toxoplasmic encephalitis, malaria, tuberculosis, leishmaniasis and schistosomiasis, often appear to be associated with unwanted Th2 immune responses Typically unwanted Th2 immune responses are associated with, or caused by, increased expression of one or more cytokines or interleukms such as IL-4 and IL-10 Administration of a formula 1 compound, or other compounds disclosed here
  • infections e g
  • a parasite infection such as malaria, Toxoplasma, Cryptospondium
  • the decreased supply of reduced glutathione may enhance phagocytosis by macrophage, possibly due to enhanced oxidative damage in infected cells or in replicating malignant cells
  • the use of a glutathione reductase inhibitor may result in improved recognition of infected or malignant cells by the immune system
  • a formula 1 compound and a flavonoid e g , a naragm flavonoid, to enhance the bioavailabihty of the formula 1 compound
  • the an effective amount of a flavonoid is administered to a subject who is receiving a formula 1 compound
  • a flavonoid such as bavachinm A, didymm ( ⁇ sosakuranet ⁇ n-7-rut ⁇ nos ⁇ de or neopon ⁇ n) flavanomarein ( ⁇ sookan ⁇ ne-7- glucoside) flavanone azme flavanone diacetylhydrazone, flavanone hydrazone, silybin, silych ⁇ stin isosilybm or siland ⁇ n
  • the flavonoid compound is typically administered with the formula 1 compound or a few hours, e g about 1 , 2 or 3 hours
  • Vaccine adiuvants The compounds disclosed herein may also be used as vaccine adjuvants with immunogens or components of immunogenic compositions to prepare antibodies capable of binding specifically to the formula 1 compounds, their metabolic products which retain immunologically recognized epitopes (sites of antibody binding) or to standard antigens that are used for vaccination against, e g , infectious agents or malignant cells
  • the immunogenic compositions therefore are useful as intermediates in the preparation of antibodies that bind to formula 1 compounds for use, e g , in diagnostic, quality control, or the like, methods or in assays for the compounds or their novel metabolic products
  • the compounds are useful for raising antibodies against otherwise non-immunogemc polypeptides, in that the compounds may serve as haptenic sites stimulating an immune response
  • the hydrolysis products of interest include products of the hydrolysis of the protected acidic and basic groups discussed above
  • the acidic or basic amides comprising immunogenic polypeptides such as albumin, keyhole limpet hemocyamin and others described below generally are useful as immunogens
  • the metabolic products described above may retain a substantial degree of immunological cross reactivity with the compounds of the invention
  • the antibodies of this invention will be capable of binding to the unprotected compounds of the invention without binding to the protected compounds, alternatively the metabolic products, will be capable of binding to the protected compounds and/or the metabolic products without binding to the protected compounds of the invention, or will be capable of binding specifically to any one or all three
  • the antibodies desirably will not substantially cross-react with naturally-occurring materials
  • Substantial cross-reactivity is reactivity under specific assay conditions for specific analytes sufficient to interfere with the assay results
  • the immunogens of this invention contain the compound of this invention presenting the desired epitope in association with an immunogenic substance.
  • association means covalent bonding to form an immunogenic conjugate (when applicable) or a mixture of non-covalently bonded materials, or a combination of the above Immunogenic substances include adjuvants such as Freund's adjuvant, immunogenic proteins such as viral, bacterial, yeast, plant and animal polypeptides, in particular keyhole limpet hemocyanm, serum albumin, bovine thyroglobulm or soybean trypsin inhibitor, and immunogenic polysaccharides.
  • adjuvants such as Freund's adjuvant, immunogenic proteins such as viral, bacterial, yeast, plant and animal polypeptides, in particular keyhole limpet hemocyanm, serum albumin, bovine thyroglobulm or soybean trypsin inhibitor, and immunogenic polysaccharides.
  • the compound having the structure of the desired epitope is covalently conjugated to an immunogenic polypeptide or polysaccharide by the use of a polyfunctional (ordinarily bifunctional) cross-linking agent
  • a polyfunctional (ordinarily bifunctional) cross-linking agent Methods for the manufacture of hapten immunogens are conventional per se Any of the methods used heretofore for conjugating haptens to immunogenic polypeptides or the like are suitably used here, taking into account the functional groups on the precursors or hydrolytic products which are available for cross-linking and the likelihood of producing antibodies specific to the epitope in question as opposed to the immunogenic substance
  • the polypeptide is conjugated to a site on the compound of the invention distant from the epitope to be recognized
  • the conjugates are prepared in conventional fashion
  • the conjugates comprise a compound of the invention attached by a bond or a linking group of 1 -100, typically, 1 - 25, more typically about 1 -10 carbon atoms to the immunogenic substance
  • the conjugates are separated from starting materials and by products using chromatography or the like, and then are sterile filtered and vialed for storage Synthetic methods to prepare hapten-car ⁇ er immunogens have been described, see e g , G T Hermanson, Bioconjugate Techniques Academic Press, 1996, pages 419- 493
  • the compounds of this invention are cross-linked for example through any one or more of the following groups a hydroxyl group a carboxyl group
  • the formula 1 compounds are used as adjuvants to enhance a subject's immune response to antigens such as proteins, peptides or virus or cell preparations
  • the formula 1 compound is administered at about the same time that the antigen is delivered to the subject, e g , within about 7 days of when the antigen is administered to the subject
  • the formula 1 compound is administered 1 , 2, 3 or 4 days before the antigen is administered to the subject
  • the formula 1 compound is administered on the same day that the antigen is administered to the subject
  • the formula 1 compound is administered 1 , 2 or 3 days after the antigen is administered
  • the formula 1 compound can be administered to the subject using any of the formulations or delivery methods described herein or in the references cited herein Aspects of the invention include compositions or formulations that comprise a formula 1 compound, one or more excipients and an antigen or antigen
  • a method comprising administering to a subject (e g , a mammal such as a human or a primate), or delivering to the subject's tissues, an effective amount of a formula 1 compound and a specific antigen
  • a subject e g , a mammal such as a human or a primate
  • a formula 1 compound e.g , a specific antigen
  • a mucosal immune response to an antigen such as a protein, peptide, polysaccharide, microorganism, tumor cell extract or lethally radiated tumor or pathogen cells (e g , antigens or cells from melanoma, renal cell carcinoma, breast cancer, prostate cancer, benign prostatic hyperplasia, virus or bacteria, or other tumor or pathogen as disclosed herein)
  • an antigen such as a protein, peptide, polysaccharide, microorganism, tumor cell extract or lethally radiated tumor or pathogen cells
  • aspects of these embodiments include enhancement of
  • the treatment may treat or ameliorate the source of the cond ⁇ t ⁇ on(s) and/or symptoms associated with the pathological cond ⁇ t ⁇ on(s) such as infection with a pathogen(s) (viruses bacteria, fungi), a malignancy, unwanted immune response, i e , an immune response that causes pathology and/or symptoms, e g , autoimmune conditions or allergy or conditions such as hypoproliferation conditions e g , normal or impaired tissue growth, or wound healing or burn healing, or in immunosuppression conditions e g , conditions characterized by an absence of a desired response and/or an inadequate degree of a desired response
  • a pathogen(s) viruses bacteria, fungi
  • a malignancy unwanted immune response
  • i e an immune response that causes pathology and/or symptoms
  • e g autoimmune conditions or allergy or conditions
  • hypoproliferation conditions e g normal or impaired tissue growth, or wound healing or burn healing
  • immunosuppression conditions e g conditions
  • the subject's hyperpro feration or malignant condition may be associated with one or more pathogens
  • pathogens For example hepatocellular carcinoma associated with HCV or HBV, Kaposi's sarcoma associated with HIV-1 or HIV- 2, T cell leukemia associated with HTLV I, Burkitt's lymphoma associated with Epstem- Barr virus or papillomas or carcinoma associated with papilloma viruses (HPV 6, HPV 11 , HPV 16, HPV 18, HPV 31 , HPV 45) or gastric adenocarcmoma or gastric MALT lymphoma associated with Helicobacter pylori infection
  • the formula 1 compound(s) is administered to a subject who has a hyperproliferation condition that appears to not be associated with a pathogen, e g , melanoma, or a cancer or precancer arising in the throat, esophagus, stomach, intestine, colon, ovary, lung, breast or central nervous

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PCT/US2000/007883 1999-03-23 2000-03-23 Immunomodulatory steroids, in particular the hemihydrate of 16.alpha.-bromoepiandrosterone WO2000056757A1 (en)

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CA002365081A CA2365081A1 (en) 1999-03-23 2000-03-23 Immunomodulatory steroids, in particular the hemihydrate of 16.alpha.-bromoepiandrosterone
BR0009476-5A BR0009476A (pt) 1999-03-23 2000-03-23 Esteróides imunomoduladores, em particular hemidrato de 16 alfa-bromoepiandrosterona
APAP/P/2001/002285A AP2001002285A0 (en) 1999-03-23 2000-03-23 Immunomodulatory steroids, in particular the hemihydrate of. 16 alpha.-bromoepiandrosterone.
NZ513803A NZ513803A (en) 1999-03-23 2000-03-23 Immunomodulatory steroids, in particular the hemihydrate of 16.alpha.-bromoepiandrosterone
JP2000606618A JP2002540119A (ja) 1999-03-23 2000-03-23 免疫修飾ステロイドとくに１６α−ブロモエピアンドロステロンのヘミハイドレート
HU0203429A HUP0203429A3 (en) 1999-03-23 2000-03-23 Immunomodulatory steroids, in particular the hemihydrate of 16.alpha.-bromoepiandrosterone, process for their preparation and pharmaceutical compositions containing them
AU39190/00A AU781997B2 (en) 1999-03-23 2000-03-23 Immunomodulatory steroids, in particular the hemihydrate of 16.alpha.-bromoepiandrosterone
RU2006133273/04A RU2417792C2 (ru) 1999-03-23 2000-03-23 Иммуномодуляторные стероиды
AT00918365T ATE259825T1 (de) 1999-03-23 2000-03-23 Hemihydrat von 16.alpha.-bromoepiandrosterone
HK02106613.2A HK1046002B (zh) 1999-03-23 2000-03-23 免疫调节性类固醇，特别是16α-溴表雄酮的半水合物
EP00918365A EP1163256B1 (en) 1999-03-23 2000-03-23 Hemihydrate of 16.alpha.-bromoepiandrosterone
IL14491600A IL144916A0 (en) 1999-03-23 2000-03-23 Immunomodulatory steroids, in particular the hemihydrate of 16-alpha-bromoepiandrosterone
DE60008353T DE60008353T2 (de) 1999-03-23 2000-03-23 Hemihydrat von 16.alpha.-bromoepiandrosterone
NO20014588A NO320801B1 (no) 1999-03-23 2001-09-21 Immunomodulerende steroider, fremgangsmate for fremstilling og anvendelse derav, samt farmasoytisk formulering.
AU2005211675A AU2005211675B2 (en) 1999-03-23 2005-09-23 Immunomodulatory steroids, in particular the hemihydrate of 16.alpha.-bromoepiandrosterone
NO20056167A NO20056167L (no) 1999-03-23 2005-12-23 Immunmodulatoriske steroider, spesielt hemihydrat av 16alfa-bromepiandrosteron

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US8022234B2 (en) 1998-11-24 2011-09-20 Harbor Biosciences, Inc. Compounds and compositions
US8106036B2 (en) 1999-03-23 2012-01-31 Harbor Biosciences, Inc. Pharmaceutical compositions-4
US7691835B2 (en) 1999-09-30 2010-04-06 Hollis-Eden Pharmaceuticals, Inc. Formulations
US8076316B2 (en) 1999-09-30 2011-12-13 Harbor Biosciences, Inc. Steroid compounds and formulations
US7241753B2 (en) 2000-02-25 2007-07-10 Loria Roger M Method of treatment of prostate cancer
US7396827B2 (en) 2000-03-16 2008-07-08 Hollis-Eden Pharmaceuticals, Inc. Pharmaceutical compositions and treatment methods
WO2002069977A1 (en) * 2001-03-01 2002-09-12 Hollis-Eden Pharmaceuticals, Inc. Use of certain steroids for treatment of blood cell deficiencies
AU2002244247B2 (en) * 2001-03-01 2007-12-13 Harbor Biosciences, Inc. Use of certain steroids for treatment of blood cell deficiencies
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WO2003024460A1 (fr) * 2001-09-14 2003-03-27 Laboratoires Mayoly Spindler Derives 7-hydroxyles et 7-cetoniques des hormones steroides 3-beta-hydroxylees pour le traitement des maladies inflammatoires ou fonctionnelles de l'intestin
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EP1539183A4 (en) * 2002-08-28 2007-04-25 Hollis Eden Pharmaceuticals THERAPEUTIC TREATMENT METHODS
US7884222B2 (en) 2003-03-04 2011-02-08 Resolution Chemicals Limited Process for the production of tibolone
US9428539B2 (en) 2013-03-28 2016-08-30 Guangzhou Cellprotek Pharmaceutical Co., Ltd. 2β,3α,5α-trihydroxy-androst-6-one and preparation methods and use thereof
WO2020163026A1 (en) 2019-02-05 2020-08-13 SD Chem, Inc. Aqueous suspension compositions, formulations, and water dispersible dry compositions comprising 16alpha-bromo-3beta-hydroxy-5alpha-androstan-17-ketone and hydrates, derivatives, and analogs thereof
US10836788B2 (en) 2019-02-05 2020-11-17 SD Chem, Inc. Aqueous suspension compositions, formulations, and water dispersible dry compositions comprising 16alpha-bromo-3beta-hydroxy-5alpha-androstan-17-ketone and hydrates, derivatives, and analogs thereof
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US11667665B2 (en) 2019-02-05 2023-06-06 SD Chem, Inc. Aqueous suspension compositions, formulations, and water dispersible dry compositions comprising 16alpha-bromo-3beta-hydroxy-5alpha-androstan-17-ketone and hydrates, derivatives, and analogs thereof
US11685762B2 (en) 2019-02-05 2023-06-27 SD Chem, Inc. Aqueous suspension compositions, formulations, and water dispersible dry compositions comprising 16alpha-bromo-3beta-hydroxy-5alpha-androstan-17-ketone and hydrates, derivatives, and analogs thereof
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NO20056167L (no) 2001-11-21
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CZ20013420A3 (cs) 2002-04-17
ES2215631T3 (es) 2004-10-16
CN1243767C (zh) 2006-03-01
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EP1163256B1 (en) 2004-02-18
KR20020003217A (ko) 2002-01-10
HK1046002B (zh) 2006-10-20
CN1355809A (zh) 2002-06-26
BR0009476A (pt) 2002-02-19
DK1163256T3 (da) 2004-06-28
JP2002540119A (ja) 2002-11-26
HK1046002A1 (en) 2002-12-20
NO20014588D0 (no) 2001-09-21
HUP0203429A3 (en) 2004-07-28
DE60008353D1 (de) 2004-03-25
AU781997B2 (en) 2005-06-23
PT1163256E (pt) 2004-07-30
IL144916A0 (en) 2002-06-30
NO20014588L (no) 2001-11-21
NZ513803A (en) 2004-06-25
RU2295534C2 (ru) 2007-03-20
AU3919000A (en) 2000-10-09
KR20070007394A (ko) 2007-01-15
AP2001002285A0 (en) 2001-12-31
CA2365081A1 (en) 2000-09-28
EP1163256A1 (en) 2001-12-19
ATE259825T1 (de) 2004-03-15
OA11850A (en) 2006-03-06
KR100717897B1 (ko) 2007-05-14
HUP0203429A2 (hu) 2003-01-28
NO320801B1 (no) 2006-01-30
DE60008353T2 (de) 2005-09-08

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